Shp2 inhibitors

ABSTRACT

The present invention relates to new compounds capable of inhibiting the activity of SHP2 phosphatase, having the general Formula (I).

FIELD OF THE INVENTION

The present invention relates to new compounds capable of inhibiting the activity of SHP2 phosphatase. Compounds of the invention can be used for the treatment of disorders associated with SHP2 deregulation. The present invention also relates to pharmaceutical compositions containing said compounds and to their method of manufacture.

BACKGROUND OF THE INVENTION

Src homology phosphotyrosine phosphatase 2 (SHP2) encoded by PTPN11 is a non-receptor protein tyrosine phosphatase (PTP) composed of a C-terminal domain, a PTP domain, and two N-terminal Src homology (N—SH2) domains, that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is a positive regulator of signalling downstream of several receptor tyrosine kynases through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol-3-kinase-AKT pathways. The protein exists in an inactive, self-inhibited conformation, stabilized by a binding network involving residues from both the N—SH2 domains and the catalytic PTP domain. Recruitment of SHP2 to an activated receptor releases the self-inhibitory conformation and leads to catalytic activation of its phosphatase domain. In addition to its function as a phosphatase, SHP2 also serves as a docking protein to recruit other signalling intermediates through its two amino terminus N—SH2 domains. Since SHP2 is a positive regulator of cellular signalling leading to proliferation, differentiation, and survival, its constitutive activation is associated with oncogenesis.

SHP2 emerged as an attractive target for therapeutic targeting in the treatment of various diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.

Both academic institutions and pharmaceutical companies have disclosed drug discovery programs exploiting SHP2 inhibitors based on different heterocyclic scaffolds.

WO2015/107493, WO2015/107494 and WO2015/107495 from Novartis disclose compounds of general formula (A) as indicated below:

Still from Novartis the compounds of general structures (B), (C), (D) and (E) indicated below are disclosed in, respectively, WO2016/203404, WO2016/203405 and WO2017/216706:

The general structure E disclosed in WO2017/216706 and the compounds therein identified are 2-amino-3H-imidazo[4,5-b]pyridine 5- or 6-thiol derivatives.

Jacobio Pharmaceuticals disclosed in WO2017/211303 and in WO2018/172984 pyrazine derivatives of structures (F) and (G) as indicated below:

Further pyridine, pyrazine and triazine compounds as allosteric SHP2 inhibitors have been recently disclosed by Revolution Medicines in WO2018/013597, WO2018/136264 and WO2019/075265. WO2018/136265 and WO2019/118909 both relate to bicyclic heteroaromatic scaffolds comprising imidazopyrazines, triazolopyrazines, pyrazolopyridine, imidazopyrimidines of general structure (H):

Pyrazolopyrazines and ring-fused pyrimidin-4-ones have been disclosed by the Board of Regents, University of Texas System, in WO2017/210134 and in WO2017/156397, respectively.

Pyrazolopyrazines were further disclosed by Relay Therapeutics in WO2018/081091, WO2018/218133, WO2018/057884 and WO2019/067843.

SHP2 therefore represents a highly attractive target for the development of novel therapies for the treatment of various diseases where it is involved. Therefore, there is the need to develop novel therapeutic agents that act as SHP2 inhibitors. The compounds of the present invention fulfill such need since they are small molecules capable of inhibiting the activity of SHP2.

DESCRIPTION OF THE INVENTION

The present invention relates to heterocyclic compounds useful as SHP2 inhibitors and for the treatment of conditions mediated by SHP2.

The inventors have found that compounds having a specific general formula surprisingly act as potent SHP2 inhibitors, as evidenced by both enzymatic and cellular IC₅₀ values for SHP2 in the low nanomolar or micromolar range.

Therefore, it is an object of the present invention a compound of Formula (I):

Wherein:

represents a single bond or a double bond; X₁ is N, S, O or NR_(3a); X₂ is N, NR_(3a) or CR_(3b); if X₁ is N then X₂ is NR_(3a); if X₁ is S, O or NR_(3a) then X₂ is N or CR_(3b); X₃ is N or CR_(x3) and R_(x3) is H, halogen or C₁₋₃alkyl; X₄ is N or CR₅; Y is S, O, NR₆, CH₂, CHF, CF₂, CHOH, C(O), SO, SO₂ or a single bond; R₁ and R₂ are each independently selected from:

-   -   hydrogen;     -   linear or branched C₁₋₁₂alkyl optionally substituted with one or         more substituents independently selected from the group         consisting of: OH, halogen, N(R₇)₂, aryl, heteroaryl, partially         unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉heterocycloalkyl and         spiro-C₃₋₈cycloalkyl ring optionally containing one heteroatom         selected from the group consisting of O, N and S, wherein each         of said aryl, heteroaryl, partially unsaturated heteroaryl,         C₃₋₉cycloalkyl, C₃₋₉ heterocycloalkyl and spiro-C₃₋₈cycloalkyl         ring is optionally further substituted with one or more groups         independently selected from the group consisting of: C(O)CH₃,         C(O)OCH₃, heteroaryl, aryl, OH, halogen, NH₂, C₁₋₆alkyl,         C₁₋₆alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl,         haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, CN, haloC₁₋₆alkoxy, C₁₋₆alkoxy,         C₅₋₇ heterocycloalkoxy and a cyclic amine selected from the         group consisting of: pyrrolidine, piperidine, morpholine,         thiomorpholine, piperazine, N-methylpyperazine and         pyrrolidin-3-yloxy; and     -   a cyclic structure selected from the group consisting of:         C₃₋₇cycloalkyl, C₃₋₉heterocycloalkyl, aryl, heteroaryl and         partially unsaturated heteroaryl, each of said cyclic structure         being optionally substituted with one ore more substituents         independently selected from the group consisting of: halogen,         C₁₋₃alkyl, C₁₋₃alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl,         C(O)OC₁₋₃alkyl, C(O)C₁₋₃alkyl, N(R₇)₂, aryl and heteroaryl, each         of said aryl or heteroaryl being optionally substituted with one         or more substituents independently selected from the group         consisting of: halogen, hydroxyl, cyano, C₁₋₃alkoxy and         C₁₋₃haloalkyl;         or R₁ and R₂ form together with the nitrogen atom to which they         are attached a cyclic amine of formula (II)

Wherein:

-   -   m and n are each independently selected from 0, 1 and 2;     -   W is absent, O, CR₈R₉, NR₁₀, S, SO or SO₂;     -   R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a),         R_(13b) are each independently selected from the group         consisting of: H, C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy,         halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally         substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy         and C₃₋₉heterocycloalkyl;     -   or any two of R_(10a), R_(10b), R_(11a), R_(11b), R_(12a),         R_(12b), R_(13a), R_(13b) which are not germinal groups, taken         together represent a single bond, a C₁₋₄alkanediyl or a         C₂₋₄alkenediyl, each of said C₁₋₄alkanediyl or C₂₋₄alkenediyl         being independently optionally substituted with one or more of         C₁₋₄alkyl and/or halogen; said single bond or said optionally         substituted C₁₋₄alkanediyl or C₂₋₄alkenediyl forming together         with the bridging atoms to which they are respectively linked a         4-10 membered saturated or partially unsaturated ring;     -   or any of R_(10a) and R_(10b), R_(11a) and R_(11b), R_(12a) and         R_(12b) or R_(13a) and R_(13b) taken together with the carbon         atom to which they are attached form a 3-7 membered saturated         ring optionally containing one or more of O, S, N and/or C(O),         the 3-7 membered saturated ring optionally being substituted         with one or more substituents each independently selected from         the group consisting of halogen, OH, haloC₁₋₆alkyl, CN,         C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C(O)OC₁₋₃alkyl and         C(O)C₁₋₃alkyl;     -   R₈ and R₉ are each independently selected from the group         consisting of: H, OH, NH₂, aryl, heteroaryl,         C₁₋₃alkylheteroaryl, C(O)NH₂, C₁₋₆alkyl, aminoC₁₋₆alkyl, NHCH₃         and NHSO₂CH₃;     -   or R₈ and R₉ taken together with the carbon atom to which they         are bound form a spiro-C₃₋₆cycloalkyl ring of formula (III) as         indicated below:

-   -   wherein:     -   p and q are each independently selected from 0, 1 and 2;     -   W₁ is absent, O, S, SO₂, CHF, CF₂ or NR_(w) and R_(w) is H,         C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆ alkyl optionally         substituted with one or more substituents each independently         selected from the group consisting of: aryl, heteroaryl, OH,         C₁₋₃alkoxy and halogen;     -   R_(14a), R_(14b), R_(15a), R_(15b), R_(16a), R_(16b), R_(17a),         R_(17b) are each independently selected from the group         consisting of: H, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl,         NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl,         halogen, OH, CN, C₁₋₃alkoxy, C₁₋₆alkyl optionally substituted         with NH₂;     -   or R_(15a) and R_(15b) taken together with the carbon atom to         which they are bound form a spiro-C₃₋₆ cycloalkyl ring         optionally containing a heteroatom selected from the group         consisting of: N, O and S;     -   or R_(15a) and R_(16a) are absent and R_(15b) and R_(16b) are         joined together to form an aryl or heteroaryl ring, each being         optionally substituted with one or more substituents each         independently selected from the group consisting of: halogen,         NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl,         NHC(O)OC₁₋₆alkyl, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, CN, OH,         C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy,         hydroxyC₁₋₆alkyl, pyrrolidine, piperidine, morpholine,         thiomorpholine, piperazine, N-methylpyperazine, C₃₋₉cycloalkyl;     -   or R_(15b) and R_(16b) are joined together to form a         C₅₋₇cycloalkyl or C₅₋₇heterocycloalkyl ring, each being         independently optionally substituted with one or more         substituents each independently selected from the group         consisting of: halogen, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,         NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, NHSOC₁₋₆alkyl,         NHSO₂C₁₋₆alkyl, CN, OH, ═O, C₁₋₆alkyl, C₁₋₆alkoxy,         haloC₁₋₆alkyl, haloC₁₋₆alkoxy and SO₂CH₃;     -   R₁₀ is H, SO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or         C₁₋₆alkyl optionally substituted with one or more groups each         independently selected from the group consisting of: OH, NH₂,         NHC(O)C₁₋₆alkyl, C₁₋₆alkoxy, halogen, cyano, aryl and         heteroaryl;     -   or R₁₀ and R_(10a) are joined together to form a         C₃₋₇heterocycloalkyl ring optionally containing another         heteroatom selected from the group consisting of: N, S and O and         optionally substituted with one or more groups each         independently selected from the group consisting of: C₁₋₆alkyl,         halogen, OH and CN;         or R₁ and R₂ form together with the nitrogen atom to which they         are attached a monocyclic or polycyclic heteroaryl or partially         unsaturated heteroaryl ring, each of said ring is optionally         substituted with one or more groups each independently selected         from the group consisting of: halogen, C₁₋₆alkyl, C₁₋₆alkoxy,         haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH, CN, SO₂C₁₋₆alkyl, NH₂ and         C(O)NH₂;         R_(3a) is H, C₁₋₆alkyl, C₁₋₆alkyl-cycloalkyl or         C₁₋₆alkyl-heterocycloalkyl, each of said groups being optionally         substituted with one or more groups independently selected from         the group consisting of: C₁₋₆alkoxy, hydroxyl, cyano,         C(O)OC₁₋₆alkyl, C(O)NH₂, C(O)NHC₁₋₆alkyl; C(O)N(C₁₋₆alkyl)₂,         SO₂C₁₋₆alkyl, SOC₁₋₆alkyl, SO₂NHC₁₋₆alkyl and SO₂N(C₁₋₆alkyl)₂;         R_(3b) is H, C₁₋₆alkyl, halogen, C(O)OC₁₋₆alkyl,         hydroxyC₁₋₆alkyl or haloC₁₋₆alkyl;         R₄ is a ring selected from the group consisting of: aryl,         heteroaryl, partially unsaturated aryl, partially unsaturated         heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₆alkylaryl,         C₁₋₆alkylheteroaryl and C₁₋₆alkylC₃₋₇cycloalkyl, each of said         ring being optionally substituted with one or more groups each         independently selected from the group consisting of: halogen,         hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkyl-N(R₇)₂, C₂₋₇alkenyl,         C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl,         cyano-C₃₋₇cycloalkyl, —SF₅, C₅₋₇heterocycloalkoxy, optionally         substituted aryl or heteroaryl, partially unsaturated         heteroaryl, optionally substituted aryloxy, optionally         substituted heteroaryl-C₁₋₆alkyl, optionally substituted         heteroaryl-C₁₋₆alkoxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)C₁₋₆alkyl,         C(O)N(R₇)₂, C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl, N(R₇)₂ and oxo;         R₅ is H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,         haloC₁₋₆alkoxy, OH, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy,         C₃₋₆heterocycloalkyl or NR_(x1)R_(x2) wherein R_(x1) and R_(x2)         are each independently H or C₁₋₆alkyl, or R_(x1) and R_(x2)         taken together with the nitrogen atom to which they are attached         form a 3-7 membered saturated ring optionally containing one or         more heteroatoms each independently selected from the group         consisting of O, S and N;         R₆ is H or C₁₋₆alkyl;         or R₄ and R₆ form together with the nitrogen atom to which they         are attached a C₃₋₉heterocycloalkyl, a heteroaryl or a partially         unsaturated heteroaryl ring, each being optionally substituted         with one or more groups independently selected from the group         consisting of: OH, halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy,         haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy,         aryl and heteroaryl;         each R₇ is independently selected from the group consisting of:         H, C₁₋₆alkyl, SO₂C₁₋₆alkyl, SOC₁₋₆alkyl, C(O)OC₁₋₆alkyl,         C(O)C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, C₁₋₆alkylaryl         and C₁₋₆alkylheteroaryl;         or two R₇ taken together with the nitrogen atom to which they         are bound form a 3 to 7 membered cyclic amine optionally         containing one additional heteroatom selected from the group         consisting of S, N and O, said 3 to 7 membered cyclic amine         being optionally substituted with one or more groups each         independently selected from the group consisting of: OH,         halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,         haloC₁₋₆alkoxy, C₃₋₇cycloalkyl and C₃₋₇cycloalkoxy; or a         pharmaceutically acceptable salt, tautomer, solvate, or         stereoisomer thereof.

As used herein, any reference to “the compound(s) of the invention”, “compound of Formula (I)” or more simply “compound(s)” includes a reference also to any pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

A preferred embodiment refers to a compound as defined above, wherein:

X₁ is N, S, O or NR₃; X₂ is N or NR₃; if X₁ is N then X₂ is NR₃; if X₁ is S, O or NR₃ then X₂ is N; when R_(15a) and R_(16a) are absent and R_(15b) and R_(16b) are joined together to form an aryl or heteroaryl ring, each aryl or heteroaryl ring is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, CN, OH, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl and haloC₁₋₆alkoxy; R₃ is H, C₁₋₆alkyl, C₁₋₆alkyl-cycloalkyl or C₁₋₆alkyl-heterocycloalkyl, each of said groups being optionally substituted with one or more groups independently selected from the group consisting of: C₁₋₆alkoxy, hydroxyl, cyano, C(O)OC₁₋₆alkyl, C(O)NH₂, C(O)NHC₁₋₆alkyl; C(O)N(C₁₋₆alkyl)₂, SO₂C₁₋₆alkyl, SOC₁₋₆alkyl, SO₂NHC₁₋₆alkyl and SO₂N(C₁₋₆alkyl)₂; R₄ is a ring selected from the group consisting of: aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₆alkylaryl, C₁₋₆alkylheteroaryl and C₁₋₆alkylC₃₋₇cycloalkyl, each of said ring being optionally substituted with one or more groups each independently selected from the group consisting of: halogen, hydroxy, cyano, C₁₋₆alkyl, C₁₋₇alkenyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, cyano-C₃₋₇cycloalkyl, —SF₅, C₅₋₇heterocycloalkoxy, optionally substituted aryl or heteroaryl, partially unsaturated heteroaryl, optionally substituted aryloxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)C₁₋₆alkyl, C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl and N(R₇)₂.

Preferably, the compound of Formula (I) is of Formula (I′), (I″) or (I′″):

All the following preferred embodiments may refer to all of Formulas (I), (I′), (I″) and (III′) and may be combined amongst themselves in any possible way that would give rise to a chemically-feasible formula.

Preferably, if X₄ is N then X₃ is CR_(x3). Preferably, if X₄ is CR₅ then X₃ is N. Preferably, if X₄ is N then X₃ is CR_(x3) and if X₄ is CR₅ then X₃ is N.

Preferably, in the compound of Formula (I), X₁ is N and X₂ is NR_(3a) or X₁ is NR₃a and X₂ is N or X₁ is NR_(3a) and X₂ is CR_(3b).

Preferably, R₁ and R₂ are each independently selected from:

-   -   hydrogen;     -   linear or branched C₁₋₁₂alkyl optionally substituted with one or         more substituents independently selected from the group         consisting of: OH, halogen, N(R₇)₂, aryl, heteroaryl, partially         unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉heterocycloalkyl and         spiro-C₃₋₈cycloalkyl ring optionally containing one heteroatom         selected from the group consisting of O, N and S, wherein each         of said aryl, heteroaryl, partially unsaturated heteroaryl,         C₃₋₉cycloalkyl, C₃₋₉ heterocycloalkyl and spiro-C₃₋₈cycloalkyl         ring is optionally further substituted with one or more groups         independently selected from the group consisting of: C(O)CH₃,         C(O)OCH₃, heteroaryl, aryl, OH, halogen, NH₂, C₁₋₆alkyl,         C₁₋₆alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl,         haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, CN, haloC₁₋₆alkoxy, C₁₋₆alkoxy,         C₅₋₇ heterocycloalkoxy and a cyclic amine selected from the         group consisting of: pyrrolidine, piperidine, morpholine,         thiomorpholine, piperazine, N-methylpyperazine and         pyrrolidin-3-yloxy; and     -   a C₃₋₇cycloalkyl, C₃₋₉heterocycloalkyl or a partially         unsaturated heteroaryl selected from bicyclo[1.1.1]pentane,         pirrolidine, piperidine, morpholine, piperazine,         2-azaspiro[3.3]heptane, azepan-2-one, 3-azaspiro[5.5]undecane,         2-azaspiro[4.5]decane, 3-azabicyclo[3.3.1]nonane,         3-oxa-7-azabicyclo[3.3.1]nonane,         6′,7′-dihydrospiro[azetidine-3,5′-pyrrolo[1,2-a]imidazole],         5-azaspiro[3.5]nonane, 1-thia-7-azaspiro[3.5]nonane 1,1-dioxide,         3-azabicyclo[3.2.0]heptane, 2-azabicyclo[2.1.1]hexane,         6-azabicyclo[3.2.1]octane, octahydroindole,         octahydro-1H-isoindole, 5-oxa-2-azaspiro[3.4]octane and         1,2,3,4-tetrahydroquinoline, each of said groups being         optionally substituted with one ore more substituents         independently selected from the group consisting of: halogen,         C₁₋₃alkyl, C₁₋₃alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl,         C(O)OC₁₋₃alkyl, C(O)C₁₋₃alkyl, N(R₇)₂, aryl and heteroaryl, each         of said aryl or heteroaryl being optionally substituted with one         or more substituents independently selected from the group         consisting of: halogen, hydroxyl, cyano, C₁₋₃alkoxy and         C₁₋₃haloalkyl;         or R₁ and R₂ form together with the nitrogen atom to which they         are attached a cyclic amine of formula (II)

Wherein:

-   -   m and n are each independently selected from 0, 1 and 2;     -   W is absent, O, CR₈R₉, NR₁₀, S, SO or SO₂;     -   R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a),         R_(13b) are each independently selected from the group         consisting of: H, C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy,         halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally         substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy         and C₃. 9heterocycloalkyl;     -   or any two of R_(10a), R_(10b), R_(11a), R_(11b), R_(12a),         R_(12b), R_(13a), R_(13b) which are not germinal groups, taken         together represent a single bond, a C₁₋₄alkanediyl or a         C₂₋₄alkenediyl, each of said C₁₋₄alkanediyl or C₂₋₄alkenediyl         being independently optionally substituted with one or more of         C₁₋₄alkyl and/or halogen; said single bond or said optionally         substituted C₁₋₄alkanediyl or C₂₋₄alkenediyl forming together         with the bridging atoms to which they are respectively linked a         4-10 membered saturated or partially unsaturated ring;     -   or any of R_(10a) and R_(10b), R_(11a) and R_(11b), R_(12a) and         R_(12b) or R_(13a) and R_(13b) taken together with the carbon         atom to which they are attached form a 3-7 membered saturated         ring optionally containing one or more of O, S, N and/or C(O),         the 3-7 membered saturated ring optionally being substituted         with one or more substituents each independently selected from         the group consisting of halogen, OH, haloC₁₋₆alkyl, CN,         C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C(O)OC₁₋₃alkyl and         C(O)C₁₋₃alkyl;     -   R₈ and R₉ are each independently selected from the group         consisting of: H, OH, NH₂, aryl, heteroaryl,         C₁₋₃alkylheteroaryl, C(O)NH₂, C₁₋₆alkyl, aminoC₁₋₆alkyl, NHCH₃         and NHSO₂CH₃;     -   or R₈ and R₉ taken together with the carbon atom to which they         are bound form a spiro-C₃₋₈cycloalkyl ring of formula (III) as         indicated below:

-   -   wherein:     -   p and q are each independently selected from 0, 1 and 2;     -   W₁ is absent, O, S, SO₂, CHF, CF₂ or NR_(w) and R_(w) is H,         C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆alkyl optionally         substituted with one or more substituents each independently         selected from the group consisting of: aryl, heteroaryl, OH,         C₁₋₃alkoxy and halogen;     -   R_(14a), R_(14b), R_(15a), R_(15b), R_(16a), R_(16b), R_(17a),         R_(17b) are each independently selected from the group         consisting of: H, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl,         NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl,         halogen, OH, CN, C₁₋₃alkoxy, C₁₋₆alkyl optionally substituted         with NH₂;     -   or R_(15a) and R_(15b) taken together with the carbon atom to         which they are bound form a spiro-C₃₋₆ cycloalkyl ring         optionally containing a heteroatom selected from the group         consisting of: N, O and S;     -   or R_(15a) and R_(16a) are absent and R_(15b) and R_(16b) are         joined together to form an aryl or heteroaryl ring, each being         optionally substituted with one or more substituents each         independently selected from the group consisting of: halogen,         NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,         NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, CN, OH, C₁₋₆alkyl,         C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, hydroxyC₁₋₆alkyl,         pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine,         N-methylpyperazine, C₃₋₉cycloalkyl;     -   or R_(15b) and R_(16b) are joined together to form a         C₅₋₇cycloalkyl or C₅₋₇heterocycloalkyl ring, each being         independently optionally substituted with one or more         substituents each independently selected from the group         consisting of: halogen, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl,         NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl,         CN, OH, ═O, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,         haloC₁₋₆alkoxy, SO₂CH₃;     -   R₁₀ is H, SO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or         C₁₋₆alkyl optionally substituted with one or more groups each         independently selected from the group consisting of: OH, NH₂,         NHC(O)C₁₋₆alkyl, C₁₋₆alkoxy, halogen, cyano, aryl and         heteroaryl;     -   or R₁₀ and R_(10a) are joined together to form a         C₃₋₇heterocycloalkyl ring optionally containing another         heteroatom selected from the group consisting of: N, S and O and         optionally substituted with one or more groups each         independently selected from the group consisting of: C₁₋₆alkyl,         halogen, OH and CN;         or R₁ and R₂ form together with the nitrogen atom to which they         are attached a monocyclic or polycyclic heteroaryl or partially         unsaturated heteroaryl ring selected from the group consisting         of: pyrrole, pyrazole, indole, benzimidazole,         2H-pyrazolo[3,4-b]pyridine, indazole,         2H-pyrazolo[3,4-c]pyridine, 6H-pyrrolo[3,4-b]pyridine,         6H-pyrrolo[3,4-b]pyrazine, 6H-pyrrolo[3,4-d]pyrimidine,         2H-pyrazolo[3,4-d]pyrimidine and 1,2,3,4-tetrahydroquinoline,         and each of said ring is optionally substituted with one or more         groups each independently selected from the group consisting of:         halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy,         OH, CN, SO₂C₁₋₆alkyl, NH₂ and C(O)NH₂;         each of R_(3a) and R_(3b) is independently H or C₁₋₆alkyl;         R₄ is a ring selected from the group consisting of: phenyl,         pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine,         quinoline, indazole, benzothiophene, isoquinoline, thiophene,         imidazopyridine, naphthyridine, quinazoline, benzimidazole,         indoline, isoindoline, 1,3-dihydroisobenzofuran,         1,2,3,4-tetrahydroquinoline,         3,4-dihydro-2H-benzo[b][1,4]oxazine,         2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, quinazolin-4(3H)-one,         indolin-2-one and 2,3-dihydro-1H-inden-1-one, indole,         dihydroquinoline, dihydroquinolin-2-one, imidazo[1,2-a]pyridine,         pyrido[2,3-b]pyrazine, indazole, benzo[c][1,2,5]oxadiazole,         pyridine-2(1H)-one and pyrrolo[2,3-b]pyridine each of said ring         being optionally substituted with one or more groups each         independently selected from the group consisting of: halogen,         hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkyl-N(R₇)₂, C₂₋₇alkenyl,         C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl,         cyano-C₃₋₇cycloalkyl, —SF₅, C₅₋₇heterocycloalkoxy, optionally         substituted aryl or heteroaryl, partially unsaturated         heteroaryl, optionally substituted aryloxy, optionally         substituted heteroaryl-C₁₋₆alkyl, optionally substituted         heteroaryl-C₁₋₆alkoxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)N(R₇)₂,         C(O)C₁₋₆alkyl, C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl, N(R₇)₂ and oxo.

Preferably, the compound of the invention has general Formula (IA), (IB) or (IC):

wherein: X₃, X₄, Y, R₄, m, n, W, R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a) and R_(13b) are as defined above.

Preferably, X₃ is N. Preferably, X₄ is CRS. Preferably, X₃ is N and X₄ is CRS.

Also preferably, R₁ and R₂ together with the nitrogen atom to which they are attached form a a cyclic amine selected from the group consisting of: aziridine, azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine, piperazine, 1,4-diazepane, 1,5-diazocane, 8-azaspiro[4.5]decane, 1,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, 1,7-diazaspiro[3.5]nonane, 1-oxa-3,7-diazaspiro[4.5]decan-2-one, (1S,4S)-2,5-diazabicyclo[2.2.2]octane, 1-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,3-dihydrospiro[indene-2,4′-piperidine], 5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine], 5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine], 5,6,7,8-tetrahydro-1,6-naphthyridine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, 3,9-diazabicyclo[4.2.1]nonane, 3,8-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 2,6-diazaspiro[3.4]octane, 3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane, 5-oxa-2,8-diazaspiro[3.5]nonane, 3,9-diazabicyclo[3.3.1]nonane, 1,2,3,4-tetrahydroisoquinoline, 1-oxa-4,8-diazaspiro[5.5]undecane, hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, 2-azaspiro[3.4]octane, 5-azaspiro[3.4]octane, 2,7-diazaspiro[4.6]undecane, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 1-oxa-9-azaspiro[5.5]undecane, 6,8-diazaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, tetrahydro-1H,4H-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole, 8-oxa-2-azaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decane, 1-oxa-4-azaspiro[5.5]undecane, 8-thia-2-azaspiro[4.5]decane 8,8-dioxide, 3′,4′-dihydro-2′H-spiro[azetidine-3,1′-pyrrolo[1,2-a]pyrazine], 2,6-diazabicyclo[3.2.2]nonane, 2,7-diazaspiro[4.4]nonane, 3H-spiro[benzofuran-2,4′-piperidine], 2-methyl-2,6-dihydro-4H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine], 4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine];

each of said cyclic amine being optionally substituted with one or more substituents each independently selected from the group consisting of: C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy, halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₉heterocycloalkyl.

Preferably, Y is S.

Preferably, R₄ is an aryl or heteroaryl ring selected from the group consisting of: phenyl, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine, quinoline, isoquinoline, indolin-2-one, indoline, isoindoline, indole, naphtyridine, benzimidazole, dihydroquinoline, dihydroquinolin-2-one, imidazo[1,2-a]pyridine, pyrido[2,3-b]pyrazine, indazole, benzo[c][1,2,5]oxadiazole, pyridine-2(1H)-one and pyrrolo[2,3-b]pyridine and each of said aryl or heteroaryl ring is optionally independently substituted with one or more groups each independently selected from the group consisting of: halogen, cyano, NH₂, CF₃, NHCH₃, NHCOCH₃, C₁₋₆alkoxy, N(CH₃)₂, —NHcycloalkyl, C₁₋₆alkyl-NH2, heteroaryl-C₁₋₆alkoxy, trifluromethoxy, C(O)N(R₇)₂ cyclopropanamine, cyclobutanamine, azetidine and pyrrolidine, each of said cyclopropanamine, cyclobutanamine, azetidine or pyrrolidine being optionally substituted with one or more groups independently selected from the group consisting of: OH, halogen, cyano and methyl. Preferably, R₄ is 14yridine, pyrimidine, pyrazine, pyridazine or pyridine, preferably 3-pyridine or even more preferably 4-pyridine.

Still preferably, R₄ is a pyridine, a pyrazine, a pyridazine or a 14yridine further substituted as indicated below:

Still preferably R₄ is bicyclic heteroaryl or partially unsaturated heteroaryl selected from:

Preferably, in any of the compounds of Formula (I), X₁ is NR_(3a), X₂ is N and X₃ is CH.

Preferably, in any of the compounds of Formula (I), X₁ is NH, X₂ is CH and X₃ is N.

Preferably, in any of the compounds of Formula (I), X₁ is S, X₂ is N and X₃ is CH.

Preferably, in any of the compounds of Formula (I), X is O or S.

Preferably, in any of the compounds of Formula (I), X₃ is N, X₄ is CR₅, Y is S or NR₆ and X₁ and X₂ are selected from: X₁ is NR_(3a) and X₂ is N, X₁ is NR_(3a) and X₂ is CR_(3b), X₁ is N and X₂ is NR_(3a) or X₁ is S and X₂ is N.

Preferably, in any of the compounds of Formula (IA), (IB) or (IC), X₃ is N and X₄ is CH.

In some preferred embodiments of Formula (I), (I′), (I″), (I′″), (IA), (IB) or (IC), R₁ and R₂ form together with the nitrogen atom to which they are attached a monocyclic or polycyclic ring system selected among those indicated below:

wherein each of the above rings can be further substituted. Preferred substituents are methyl, amino, aminomethyl, F, Cl, Br.

In some embodiments of Formula (I), (I′), (I″) or (I′″), R₁ is H and R₂ is selected from:

wherein each of the above groups can be further substituted. Preferred substituents are methyl, amino, aminomethyl, F, Cl, Br, phenyl and benzyl.

In a preferred embodiment the present invention provides a compound of Formula (I)

Wherein:

represents a single bond or a double bond; X₁ is N, S, O or NR_(3a); X₂ is N, NR₃a or CR_(3b); if X₁ is N then X₂ is NR_(3a); if X₁ is S, O or NR_(3a) then X₂ is N or CR_(3b); X₃ is N or CR_(x3) and R_(x3) is H, halogen or C₁₋₃alkyl; X₄ is Nor CR₅; wherein if X₄ is N then X₃ is CR_(x3) and if X₄ is CR₅ then X₃ is N; Y is S, O, NR₆, CH₂, CHF, CF₂, CHOH, C(O), SO, SO₂ or a single bond; R₁ and R₂ are each independently selected from:

-   -   hydrogen;     -   linear or branched C₁₋₁₂alkyl optionally substituted with one or         more substituents independently selected from the group         consisting of: OH, halogen, N(R₇)₂, aryl, heteroaryl, partially         unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉heterocycloalkyl and         spiro-C₃₋₈cycloalkyl ring optionally containing one heteroatom         selected from the group consisting of O, N and S, wherein each         of said aryl, heteroaryl, partially unsaturated heteroaryl,         C₃₋₉cycloalkyl, C₃₋₉ heterocycloalkyl and spiro-C₃₋₈cycloalkyl         ring is optionally further substituted with one or more groups         independently selected from the group consisting of: C(O)CH₃,         C(O)OCH₃, heteroaryl, aryl, OH, halogen, NH₂, C₁₋₆alkyl         optionally substituted with N(R₇)₂, C₁₋₃alkylaryl,         C₁₋₃alkylheteroaryl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, CN,         haloC₁₋₆alkoxy, C₁₋₆alkoxy, C₅₋₇heterocycloalkoxy and a cyclic         amine selected from the group consisting of: pyrrolidine,         piperidine, morpholine, thiomorpholine, piperazine,         N-methylpyperazine and pyrrolidin-3-yloxy; and     -   a C₃₋₇cycloalkyl, C₃₋₉heterocycloalkyl or a partially         unsaturated heteroaryl selected from bicyclo[1.1.1]pentane,         pirrolidine, piperidine, morpholine, piperazine,         2-azaspiro[3.3]heptane, azepan-2-one, 3-azaspiro[5.5]undecane,         2-azaspiro[4.5]decane, 3-azabicyclo[3.3.1]nonane,         3-oxa-7-azabicyclo[3.3.1]nonane,         6′,7′-dihydrospiro[azetidine-3,5′-pyrrolo[1,2-a]imidazole],         5-azaspiro[3.5]nonane, 1-thia-7-azaspiro[3.5]nonane 1,1-dioxide,         3-azabicyclo[3.2.0]heptane, 2-azabicyclo[2.1.1]hexane,         6-azabicyclo[3.2.1]octane, octahydroindole,         octahydro-1H-isoindole, 5-oxa-2-azaspiro[3.4]octane and         1,2,3,4-tetrahydroquinoline, each of said groups being         optionally substituted with one ore more substituents         independently selected from the group consisting of: halogen,         C₁₋₃alkyl optionally substituted with N(R₇)₂, C₁₋₃alkylaryl,         C₁-3alkylheteroaryl, C(O)OC₁₋₃alkyl, C(O)C₁₋₃alkyl, N(R₇)₂, aryl         and heteroaryl, each of said aryl         or heteroaryl being optionally substituted with one or more         substituents independently selected from the group consisting         of: halogen, hydroxyl, cyano, C₁₋₃alkoxy and C₁₋₃haloalkyl; or         R₁ and R₂ together with the nitrogen atom to which they are         attached form a a cyclic amine selected from the group         consisting of: aziridine, azetidine, pyrrolidine, piperidine,         azepane, morpholine, thiomorpholine, piperazine, 1,4-diazepane,         1,5-diazocane, 8-azaspiro[4.5]decane, 1,7-diazaspiro[3.5]nonane,         2,6-diazaspiro[3.5]nonane,         4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,         5,6,7,8-tetrahydro-1,7-naphthyridine,         4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine,         1,7-diazaspiro[3.5]nonane, 1-oxa-3,7-diazaspiro[4.5]decan-2-one,         (1S,4S)-2,5-diazabicyclo[2.2.2]octane,         1-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane,         1,3-dihydrospiro[indene-2,4′-piperidine],         5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine],         5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine],         5,6,7,8-tetrahydro-1,6-naphthyridine,         octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole,         3,9-diazabicyclo[4.2.1]nonane, 3,8-diazabicyclo[3.2.1]octane,         3-azabicyclo[3.1.0]hexane, 2,6-diazaspiro[3.4]octane,         3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane,         5-oxa-2,8-diazaspiro[3.5]nonane, 3,9-diazabicyclo[3.3.1]nonane,         1,2,3,4-tetrahydroisoquinoline,         1-oxa-4,8-diazaspiro[5.5]undecane,         hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide,         2-azaspiro[3.4]octane, 5-azaspiro[3.4]octane,         2,7-diazaspiro[4.6]undecane,         4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine,         1-oxa-9-azaspiro[5.5]undecane, 6,8-diazaspiro[3.5]nonane,         6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane,         tetrahydro-1H,4H-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole,         8-oxa-2-azaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decane,         1-oxa-4-azaspiro[5.5]undecane, 8-thia-2-azaspiro[4.5]decane         8,8-dioxide,         3′,4′-dihydro-2′H-spiro[azetidine-3,1′-pyrrolo[1,2-a]pyrazine],         3,9-diazabicyclo[4.2.1]nonane, 2,6-diazabicyclo[3.2.2]nonane,         2,7-diazaspiro[4.4]nonane, 3H-spiro[benzofuran-2,4′-piperidine],         2-methyl-2,6-dihydro-4H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine],         4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine];         each of said cyclic amine being optionally substituted with one         or more substituents each independently selected from the group         consisting of: C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy, halogen,         NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally substituted aryl,         hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy,         C₃₋₉heterocycloalkyl;         or R₁ and R₂ form together with the nitrogen atom to which they         are attached a monocyclic or polycyclic heteroaryl or partially         unsaturated heteroaryl ring selected from the group consisting         of: pyrrole, pyrazole, indole, benzimidazole,         2H-pyrazolo[3,4-b]pyridine, indazole,         2H-pyrazolo[3,4-c]pyridine, 6H-pyrrolo[3,4-b]pyridine,         6H-pyrrolo[3,4-b]pyrazine, 6H-pyrrolo[3,4-d]pyrimidine,         2H-pyrazolo[3,4-d]pyrimidine and 1,2,3,4-tetrahydroquinoline,         and each of said ring is optionally substituted with one or more         groups each independently selected from the group consisting of:         halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy,         OH, CN, SO₂C₁₋₆alkyl, NH₂ and C(O)NH₂;         each of R_(3a) and R_(3b) is independently H or C₁₋₆alkyl;         R₄ is a ring selected from the group consisting of: phenyl,         pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine,         quinoline, indazole, benzothiophene, isoquinoline, thiophene,         imidazopyridine, naphthyridine, quinazoline, benzimidazole,         indoline, isoindoline, 1,3-dihydroisobenzofuran,         1,2,3,4-tetrahydroquinoline,         3,4-dihydro-2H-benzo[b][1,4]oxazine,         2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, quinazolin-4(3H)-one,         indolin-2-one, and 2,3-dihydro-1H-inden-1-one, each of said ring         being optionally substituted with one or more groups each         independently selected from the group consisting of: halogen,         hydroxy, cyano, C₁₋₆alkyl optionally substituted with N(R₇)₂,         C₂₋₇alkenyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy,         C₃₋₇cycloalkyl, cyano-C₃₋₇cycloalkyl, —SF₅,         C₅₋₇heterocycloalkoxy, optionally substituted aryl or         heteroaryl, partially unsaturated heteroaryl, optionally         substituted aryloxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)C₁₋₆alkyl,         C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl and N(R₇)₂;         R₅ is H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,         haloC₁₋₆alkoxy, OH, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy,         C₃₋₆heterocycloalkyl or NR_(x1)R_(x2) wherein R_(x1) and R_(x2)         are each independently H or C₁₋₆alkyl, or R_(x1) and R_(x2)         taken together with the nitrogen atom to which they are attached         form a 3-7 membered saturated ring optionally containing one or         more heteroatoms each independently selected from the group         consisting of O, S and N;         R₆ is H or C₁₋₆alkyl;         or R₄ and R₆ form together with the nitrogen atom to which they         are attached a C₃₋₉heterocycloalkyl, a heteroaryl or a partially         unsaturated heteroaryl ring, each being optionally substituted         with one or more groups independently selected from the group         consisting of: OH, halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy,         haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy,         aryl and heteroaryl;         each R₇ is independently selected from the group consisting of:         H, C₁₋₆alkyl, SO₂C₁₋₆alkyl, SOC₁₋₆alkyl, C(O)OC₁₋₆alkyl,         C(O)C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, C₁₋₆alkylaryl         and C₁₋₆alkylheteroaryl;         or two R₇ taken together with the nitrogen atom to which they         are bound form a 3 to 7 membered cyclic amine optionally         containing one additional heteroatom selected from the group         consisting of S, N and O, said 3 to 7 membered cyclic amine         being optionally substituted with one or more groups each         independently selected from the group consisting of: OH,         halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,         haloC₁₋₆alkoxy, C₃₋₇cycloalkyl and C₃₋₇cycloalkoxy; or a         pharmaceutically acceptable salt, tautomer, solvate, or         stereoisomer thereof.

In a preferred embodiment of the invention, the compounds are selected from the following list:

-   4-methyl-1-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   (8-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)methanamine -   (R)-8-(6-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine -   2-(1,7-diazaspiro[3.5]nonan-7-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine -   1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   2-(4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one -   4-methyl-1-(6-(phenylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(5-((2-(trifluoromethyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-(trifluoromethyl)benzonitrile -   1-(5-((2,4-difluorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2,3-difluorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   2-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzonitrile -   1-(5-((2-methoxyphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-3-amine -   N-(piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine -   1-(5-((2-bromophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((4-chloro-2-methylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2,3-dimethylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   2-(1,7-diazaspiro[3.5]nonan-1-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine -   4-methyl-1-(5-((6-(trifluoromethyl)pyridin-2-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(5-((3-(2-methylthiazol-4-yl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(6-(quinolin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-([1,1′-biphenyl]-3-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-methyl-1-(5-(naphthalen-1-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(5-(quinolin-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-((1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2-bromopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-(isoquinolin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-methyl-1-(5-(quinoxalin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-((2-chlorothiophen-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-methyl-1-(5-((2-(pentafluoro-16-sulfaneyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-methyl-1-(5-(naphthalen-2-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   4-methyl-1-(5-(quinolin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-(isoquinolin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-methyl-1-(5-((3-(pentafluoro-16-sulfaneyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   3-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzoic     acid -   4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzoic     acid -   (3S,4S)-3-methyl-8-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine -   4-methyl-1-(5-((8-(trifluoromethyl)quinolin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine -   1-(5-((2-chlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chlorobenzoic     acid -   2-(3-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)phenyl)acetic     acid -   1-(5-((1,8-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   1-(5-((3-chloro-2-methylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   1-(5-((2-isopropylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine -   (S)-1′-(6-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   2-(9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine -   2-(3,9-diazabicyclo[4.2.1]nonan-3-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine -   N-(5-azaspiro[3.5]nonan-8-yl)-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine -   (8-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)methanamine -   N-((5-phenylpyrrolidin-3-yl)methyl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine -   (S)-1′-(6-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoro-1-methylindolin-2-one -   (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoroindolin-1-yl)ethan-1-one -   (S)-1′-(5-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2-(trifluoromethyl)pyridine     1-oxide -   (R)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine -   1-(2-((2,3-dichlorophenyl)thio)-7H-purin-8-yl)-4-methylpiperidin-4-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)—N-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)acetamide -   (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (R)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine -   (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-ol -   (S)-1′-(5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (R)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine -   (S)-1′-(5-((4-(trifluoromethyl)pyrimidin-5-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-8-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2H-benzo[b][1,4]oxazin-3(4H)-one -   (S)-1′-(5-((3-chloropyrazin-2-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine -   (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoroindolin-2-one -   (R)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[furo[3,2-b]pyridine-2,4′-piperidin]-3-amine -   (S)-1′-(6-((1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidin-3-ol -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-3-chloro-1-methylpyridin-2(1H)-one -   (S)-1′-(6-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-6-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-4-chlorobenzo[d]oxazol-2(3H)-one -   (S)-6-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one -   (S)-5-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,4-dihydroquinolin-2(1H)-one -   (S)-1′-(5-((2,3-dichloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-8-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one -   (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine -   (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-(quinolin-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-7-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)benzo[d]oxazol-2(3H)-one -   (S)-1′-(5-(quinoxalin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloro-2-morpholinopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloro-2-(3-methoxyazetidin-1-yl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-6-fluoro-1′-(6-((3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((2-amino-5-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-6-fluoro-1′-(6-((3-fluoropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((2-amino-3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonitrile -   (S)-6-fluoro-1′-(5-(imidazo[1,2-a]pyridin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((1H-indol-6-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-(pyrido[2,3-b]pyrazin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((3-chloro-2-methylpyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine -   (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(6-((1H-indol-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-ethoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2-(methylamino)nicotinonitrile -   (S)-1′-(5-((2-methyl-2H-indazol-7-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(6-((2-amino-3-methylpyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-ol -   (R)—N—((S)-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide -   (S)-1′-(5-((3-aminopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-(dimethylamino)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-(thieno[3,2-b]pyridin-7-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-(benzo[c][1,2,5]oxadiazol-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-2-amino-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)nicotinonitrile -   (S)-5-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)quinoxalin-2(1H)-one -   (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)picolinonitrile -   (S)-1′-(5-((5-fluoroquinolin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((6-methoxy-1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-4H-pyrido[1,2-a]pyrimidin-4-one -   (S)-1′-(5-((2-amino-3-fluoropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-N-methylpicolinamide -   (S)-1′-(5-((2-(pyrrolidin-1-yl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-(trifluoromethoxy)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-((2-methyloxazol-4-yl)methoxy)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-6-bromo-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-6-bromo-1′-(5-((2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-2-methyl-2,6-dihydro-4H-spiro[cyclopenta[c]pyrazole-5,4′-piperidin]-4-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)pyridazin-3(2H)-one -   (S)-1′-(5-((2-(oxazol-2-ylmethoxy)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-methoxypyridazin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((4-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)pyridin-2(1H)-one -   (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile -   (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-5-chloropyridin-2-ol -   (S)-1′-(5-((5-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-(1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)methanol -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloro-2-(ethylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((3-chloropyridazin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(7-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((5-(aminomethyl)-2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-(1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-5-yl)methanol -   methyl     (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate -   (S)-1′-(5-((8-methyl-1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile -   (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-2-chloro-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine -   (S)-1′-(6-chloro-5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (R)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile -   (S)-1′-(5-((1-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((2-chloro-3-(trifluoromethyl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine -   (S)-1′-(5-((2-(methylamino)-3-(trifluoromethyl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(5-((6-amino-2,3-dichloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine -   (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine -   (3S,4S)-8-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine -   (S)-1′-(5-((6-amino-2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine     or a pharmaceutically acceptable salt, tautomer, solvate, or     stereoisomer thereof.

The invention further provides a process for the preparation of compounds of the invention. In particular, it is a further object of the invention a process for the synthesis of the compound of Formula (I) or the pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, said process comprising at least one of the following steps:

a) reacting a compound of formula (A) with a compound of formula R₄YH in the presence of a transition metal catalyst or under photochemical conditions, wherein said transition metal catalyst is preferably a palladium or copper catalyst, such as Pd₂(dba)₃, Pd(PPh₃)₄ and CuI:

or b) when in said compound of Formula (I) Y is S, reacting in a first step a compound of formula (A) with 2-ethylhexyl 3-mercaptopropanoate in the presence of a palladium catalyst, and further reacting in a second step the product from the first step with a compound of formula R₄X, wherein X is bromide, chloride, iodide or triflate, in the presence of a palladium catalyst, wherein said first and second steps are carried out in the presence of a tertiary amine, preferably DIPEA or TEA, and wherein the palladium catalyst in said first and/or second step is preferably Pd₂(dba)₃ or Pd(PPh₃)₄:

or c) when in said compound of Formula (I) Y is a bond, reacting a compound of formula (A) with R₄-boronic acid in the presence of a palladium catalyst, preferably Pd(PPh₃)₄, and a base:

or d) reacting a compound of formula (B), wherein Lg is a leaving group selected from the group consisting of halogen, SO₂Me and SOMe, with an amine of formula R₁R₂NH at temperature range of about 100° C. to about 120° C.:

wherein in each of said a), b) c) or d) steps, if X₁ or X₂ is NH, it can be optionally protected for example as a trimethylsilylethoxymethyl (SEM) derivative.

In a preferred embodiment, compounds of Formula (I′) and (I″) may respectively be prepared according to one of the following synthetic schemes:

Compounds of Formula (I′) may be prepared from compounds of formula (C1) through cross coupling with the appropriate compound of formula R₄YH. Same procedure applies to the synthesis of a compound of Formula (I″) from a compound of formula (C′1). The compound of formula R₄YH may be an aryl or heteroaryl derivative such as aryl bromide, aryl chloride, aryl iodide or other suitable activating groups (e.g. triflates, mesylates, tosylates, nonaflates), aryl alcohol, arylthio, aryl-boronate, aryl-stannate, heteroaryl-amine, heteroaryl bromide, heteroaryl chloride, heteroaryl iodide or other suitable activating groups (e.g. triflates, mesylates, tosylates, nonaflates), heteroaryl alcohol, heteroaryl-thio, heteroaryl-boronate, heteroaryl-stannate, heteroaryl-amine. This reaction may be conducted under suitable acid or base conditions, in the presence or absence of a transition metal such as palladium, under different temperature conditions. Alternatively, a compound of Formula (I′) can be prepared by reacting compound of formula (C2) with an amine R₁R₂NH under appropriate conditions, in the presence or absence of a base such as diisopropylethylamine. Similarly, the compounds of Formula (I″) can be prepared from compounds of formula (C′2).

Compounds of the invention may be used in the form of prodrugs. A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the “parent drug” or “parent molecule”, i.e. the compound of the invention) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.

The invention also includes all suitable isotopic variations of a compound of the invention. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certain isotopic variations of the disclosure, for example, those in which a radioactive isotope such as 3H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Further, substitution with isotopes such as deuterium ²H, may afford certain therapeutic advantages resulting from greater metabolic stability. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods and the preparations described in the Descriptions and in the Examples hereafter using appropriate isotopic variations of suitable reagents.

The present invention includes within its scope solvates of the compounds of Formula (I), (IA) and (IB) or of the relative salts, for example, hydrates, alcoholates and the like.

In addition, the compounds disclosed herein may exist as tautomers and all tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example, a reference to 2-hydroxypyridine also includes pyridin-2-one as its tautomeric form and a reference to 4-hydroxypyridine also includes pyridin-4-one as its tautomeric form. Similarly, a reference to a hydroxypyrimidine derivative also includes the corresponding pyrimidinone tautomer, a reference to 2,4-dihydro-3H-1,2,4-triazol-3-one also includes the corresponding 1H-1,2,4-triazol-5-ol, and so on. In particular, Formula (I) encompasses compounds of structures indicated below:

wherein X₁, X₂, X₃ and X₄ are as defined hereinabove.

The compounds disclosed herein may exist in different isomeric forms, all of which are encompassed by the present invention. In particular, any reference to the compound of the present invention is intended to include all its possible resonance forms.

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures and are intended to be encompassed by the scope of the invention. In particular, “pure stereoisomeric form” or “stereoisomerically pure” indicate a compound having stereoisomeric excess of at least 80%, preferably of at least 85%. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts or by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. The term “enantiomerically pure” shall be interpreted in a similar way, having regard to the enantiomeric ratio.

When any variable (e.g. R₁ and R₂, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted” should be taken to be equivalent to the phrase “unsubstituted or substituted with one or more substituents” and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents.

According to the invention, “

” represent a single or a double bond. It will be understood by the skilled person that the two bonds indicated as “

” in Formula (I) cannot both be double bonds. The two bonds indicated as “

” in Formula (I) may be two single bonds or one single bond and one double bond. In particular, general Formula (I) encompasses the two structures indicated below:

wherein X₁, X₂, X₃ and X₄ are as defined above.

The expressions “one or more substituents” and “one or more groups” refer to in particular to 1, 2, 3, 4 or more substituents, in particular to 1, 2, 3 or 4 substituents, more in particular 1, 2 or 3 substituents.

As used herein “Y is a single bond” indicates that, in the general Formula (I) or Formula (II), R₄ is directly linked via a single bond to the heteroaromatic scaffold.

As used herein, if two residues taken together represent a single bond, this means that the two atoms to which they are attached are connected by a single bond or by an additional bond thus forming a multiple bond.

As used herein “W is absent” indicates that in the cyclic amine of formula (II) the carbon atoms bearing, respectively, R_(10a), R_(10b) and R_(11a), R_(11b) are directly connected as in the following general structure:

As used herein “W₁ is absent” indicates that in the cyclic amine of formula (III) the carbon atoms bearing, respectively R_(16a), R_(16b) and R_(17a), R₁7b, are directly connected as in the following general structure:

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C₁₋₁₂alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons in a linear or branched arrangement and specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, and so on. As another example, “C₁₋₆alkyl” is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement and specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, and so on. Preferably, “C₁₋₁₂alkyl” and “C₁₋₆alkyl” refer to “C₁₋₄alkyl” or “C₁₋₃alkyl”. “C₁₋₄alkyl” is defined to include groups having 1, 2, 3 or 4 carbons in a linear or branched arrangement. For example, “C₁₋₄ alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, and so on. “C₁₋₃alkyl” is defined to include groups having 1, 2, or 3 carbons in a linear or branched arrangement. For example, “C₁₋₃ alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, and so on. Preferred alkyl groups are methyl, ethyl, i-propyl, t-butyl or i-butyl.

The term “alkenyl” as used herein refers to a straight or branched hydrocarbon chain which includes one or more double bonds in the normal chain. For example, C₂₋₇alkenyl refers to a straight or branched hydrocarbon chain containing from 2 to 7 carbon atoms which include 1 to 3 double bonds in the normal chain. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like.

As used herein, “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above. C₁₋₆ alkoxy group is preferably a linear or branched C₁₋₄ alkoxy group, more preferably a C₁₋₃alkoxy group, still more preferably a C₁₋₂ alkoxy group. Examples of suitable alkoxy groups include, but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy or t-butoxy.

Preferred alkoxy groups include methoxy, ethoxy and t-butoxy.

As used herein, the terms “haloC₁₋₆alkyl”, “haloC₁₋₆alkoxy” and variants thereof such as “C₁₋₆haloalkyl” mean a C₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. HaloC₁₋₆alkoxy group is preferably a linear or branched haloC₁₋₄alkoxy group, more preferably a haloC₁₋₃alkoxy group, still more preferably a haloC₁₋₂alkoxy group, for example OCF₃, OCHF₂, OCH₂F, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially OCF₃ or OCHF₂. HaloC₁₋₆alkyl group is preferably a linear or branched haloC₁₋₃alkyl group, more preferably a haloC₁₋₂alkyl group for example, CF₃, CHF₂, CH₂F, CH₂CH₂F, CH₂CHF₂, CH₂CF₃ or CH(CH₃)CF₃, and most especially CF₃, CHF₂ or CH(CH₃)CF₃.

As used herein, the term “hydroxyC₁₋₆alkyl” means a C₁₋₆alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferably, the hydroxyC₁₋₆alkyl is a hydroxyC₁₋₄alkyl, meaning a C₁₋₄alkyl group in which one or more (in particular, 1 to 2) hydrogen atoms have been replaced by hydroxy groups. Illustrative examples include, but are not limited to CH₂OH, CH₂CH₂OH, CH(CH₃)OH and CHOHCH₂OH.

As used herein, the terms “heteroaryl-C₁₋₆alkoxy” mean a C₁₋₆alkoxy group in which one hydrogen atom is replaced by an heteroaryl group, wherein said aryl or heteroaryl can be further substituted by, for example, methyl, halogen, hydroxyl or amine.

As used herein, the term “aminoC₁₋₆alkyl” means a C₁₋₆alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by small amino groups, such as NH₂, NHCH₃, N(CH₃)₂ and the like.

As used herein, the term “aryl” or “aromatic ring” means a monocyclic or polycyclic aromatic ring comprising carbon atoms and hydrogen atoms. If indicated, such aromatic ring may include one or more heteroatoms, then also referred to as “heteroaryl” or “heteroaromatic ring”, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, preferably nitrogen. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the present invention, a heteroaryl group need only have some degree of aromatic character. Preferably, the ring component of aryl or heteroaryl groups comprises 5 or 6 members (i.e. atoms). Illustrative examples of aryl groups are optionally substituted phenyls. Illustrative examples of heteroaryl groups according to the invention include optionally substituted thiophene, oxazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine, pyridine and pyridine N-oxide. Thus, examples of monocyclic aryl optionally containing one or more heteroatoms, for example one or two heteroatoms, are a 5- or 6-membered aryl or heteroaryl group such as, but not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxadiazolyl and oxazolyl. Examples of polycyclic aromatic ring, optionally containing one or more heteroatoms, for example one or two heteroatoms, are a 8-10 membered aryl or heteroaryl group such as, but not limited to, benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, indolyl, indolinyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolyl, quinazolinyl, quinolyl, quinoxalinyl, quinolizinyl, naphtyl, naphthyridinyl and phthalazinyl. Other examples of polycyclic heteroaromatic rings according to the invention are 2H-pyrazolo[3,4-b]pyridine, indazole, 2H-pyrazolo[3,4-c]pyridine, 6H-pyrrolo[3,4-b]pyridine, 6H-pyrrolo[3,4-b]pyrazine, 6H-pyrrolo[3,4-d]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, 1,5-naphthyridine. A preferred aryl according to the present invention is phenyl. A preferred heteroaryl according to the present invention is pyridyl.

The expressions “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted aryloxy”, “optionally substituted heteroaryl-C₁₋₆alkyl”, “optionally substituted heteroaryl-C₁₋₆alkoxy” generically refer to aryl, heteroaryl or aryloxy groups wherein the aromatic or heteroaromatic ring may be substituted with one or more substituents. Examples of said substituents include alkyl, alkoxy, amino, trifluoromethyl, aryl, heteroaryl, hydroxyl, carboxyalkyl and the like.

As used herein, heterocycle, heterocyclic compound or ring structure, heterocycloalkyl and variants thereof refer to a saturated monocyclic or polycyclic compound that has atoms of at least two different elements as members of its ring(s).

Polycyclic aromatic or heteroaromatic rings can also have a partially unsaturated structure and can thus be derived from the partially hydrogenated analogues of the before-listed aryl or heteroaryl groups but also from an aryl or heteroaryl ring fused with a cycloalkyl or heterocycloalkyl ring. Said rings might also contain a group selected from SO, SO₂ and C═O. Examples of said partially unsaturated polycyclic aryl or heteroaryl derivatives include 2,3-dihydro-1H-indene, 2,3-dihydro-1H-inden-1-one, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, isoindoline, dihydroquinazoline, dihydroquinoxaline, 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 1,3-dihydroisobenzofuran, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, quinazolin-4(3H)-one, 4,5,6,7-tetrahydro-1H-indazole, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 6′,7′-dihydrospiro[azetidine-3,5′-pyrrolo[1,2-a]imidazole], 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, indolin-2-one, 1,2,3,4-tetrahydro-1,5-naphthyridine, 3′,4′-dihydro-2′H-spiro[azetidine-3,1′-pyrrolo[1,2-a]pyrazine], 3,4-dihydroquinolin-2(1H)-one, 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, quinoxalin-2(1H)-one, 4H-pyrido[1,2-a]pyrimidin-4-one and the like.

As used herein, the term “aryloxy” represents an aryl group as defined above attached through an oxygen bridge. Aryloxy therefore encompasses the definitions of aryl and heteroaryl above. Illustrative examples include phenoxy, naphtyloxy, pyridinyloxy and so on.

As used herein, the term “C₃₋₉heterocycloalkyl” is a saturated monocyclic or bicyclic ring system, of 3 to 9 members which contains one or more heteroatoms selected from N, O and S and/or contains a group selected from SO, SO₂ and C═O. In a particular embodiment of the invention, the C₃₋₉heterocycloalkyl group is restricted to a C₃₋₈heterocycloalkyl or to a C₅₋₇heterocycloalkyl group. Examples include, but are not limited to azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, pyrrolidinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, azocanyl, oxazocanyl, 8-oxabicyclo[3.2.1]octane, 2-oxabicyclo[2.1.1]hexane, hexahydrofuro[2,3-b]furane, 2-azaspiro[3.3]heptane, azepan-2-one, 3-azaspiro[5.5]undecane, 2-azaspiro[4.5]decane, 3-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 5-azaspiro[3.5]nonane, 1-thia-7-azaspiro[3.5]nonane 1,1-dioxide, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[2.1.1]hexane, 6-azabicyclo[3.2.1]octane, octahydroindole, octahydro-1H-isoindole, 5-oxa-2-azaspiro[3.4]octane, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, thiolane 1,1-dioxide, 2-oxa-9-azaspiro[5.5]undecane, oxazocanyl 2-oxabicyclo[2.1.1]hexane, 7-azabicyclo[2.2.1]heptane, octahydro-4aH-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine. Preferred are saturated cyclic hydrocarbons with 3, 4 or 5 carbon atoms and 1 oxygen or 1 nitrogen atom. Examples include oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, piperidinyl or pyrrolidinyl

As used herein, the term “C₅₋₇heterocycloalkoxy” represents a C₅₋₇heterocycloalkyl group as defined above attached through an oxygen bridge. Illustrative examples include the oxetan-3-yloxy, azetidin-3-yloxy, pyrrolidin-3-yloxy and so on.

A substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.

As used herein, the term “C₁₋₆ alkanediyl” as group or part of a group defines bivalent straight or branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms. C₁₋₆ alkanediyl group, is preferably a C₁₋₄ alkanediyl group, a C₁₋₃ alkanediyl or more preferably a C₁₋₂ alkanediyl. Examples include, but are not limited to methanediyl, ethanediyl, propanediyl, butanenediyl, pentanediyl and hexanediyl. Preferred are methanediyl, ethanediyl and propanediyl.

As used herein, the term “C₂₋₇alkenediyl” as group or as part of a group defines bivalent straight or branched (carbon number limitation permitting) chained unsaturated hydrocarbon radicals having from 2 to 7 carbon atoms. C₂₋₇ alkenediyl group, is preferably a C₂₋₄ alkenediyl group. Non limiting examples of C₂₋₇alkenediyl are: —C═CH—, —CH═C(CH₃)CH₂—, —CH═CH—CH₂—.

As used herein, the term or “C₃₋₉cycloalkyl” means saturated cyclic hydrocarbon (cycloalkyl) with 3, 4, 5, 6, 7, 8 or 9 ring atoms and is generic for example to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl. As used herein, the term “C₃₋₈ cycloalkyl” means saturated cyclic hydrocarbon (cycloalkyl) with 3, 4, 5, 6, 7 or 8 carbon atoms and in a particular embodiment of the invention, the C₃₋₈cycloalkyl is restricted to a C₃₋₇ cycloalkyl, such as a 5 or 6 membered cycloalkyl. Depending on the dimension of the ring, it can be also of bicyclic structure, such as a bicycle[3.1.0]hexane, bicycle[4.1.0]heptane, octahydropentalene, bicyclo[1.1.1]pentane, and the like. In a particular embodiment of the invention, the 3-11 membered saturated ring” is restricted to a “3-9 membered saturated ring” or a “3-7 membered saturated ring”.

As used herein, the expression “4-10 membered partially unsaturated ring” indicates a ring containing 4 to 10 carbon atoms and at least one double bond. Depending on the dimension of the ring, it can be of a cyclic or bicyclic structure. Each of the above rings may optionally contain one or more heteroatoms, such that at least one carbon is replaced by a heteroatom selected from N, O and S, in particular from N and O. Examples include, but are not limited to cyclopentenyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclohexa-1,4-dienyl, cycloheptenyl, cyclohepta-1,4-dienyl, dihydrofuranyl, dihydropyrrole, dihydropyranyl, hexahydro-1H-cyclopenta[c]furanyl and the like.

It should be noted that different isomers of the various heterocycles may exist within the definitions as used throughout the specification. For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

It should also be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, 4-pyridyl.

As used herein, the term “halogen” refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are preferred.

The term “heteroatom” refers to an atom other than carbon or hydrogen in a ring structure or a saturated backbone as defined herein. Typical heteroatoms include N(H), O, S.

As used herein, “cycloalkoxy” represents a cycloalkyl group of the indicated number of carbons attached through an oxygen bridge. “Cycloalkoxy” therefore encompasses the definitions of cycloalkyl above and is preferably a C₁₋₆alkoxy as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

The expression “cyano-C₃₋₇cycloalkyl” refers to one or more cyano groups appended to a C₃₋₇cycloalkyl.

The term “C₁₋₆alkylaryl” as used herein indicates one or more aryl groups appended to a C₁₋₆alkyl radical. Preferably, the C₁₋₆alkylaryl is a “C₁₋₃alkylaryl”, i.e. one or more aryl groups appended to a C₁₋₃alkyl radical. As used herein, the term “C₁₋₆alkylheteroaryl” indicates one or more heteroaryl groups appended to a C₁₋₆alkyl radical. Preferably, the C₁₋₆alkylheteroaryl is a “C₁₋₃alkylheteroaryl”, i.e. one or more heteroaryl groups appended to a C₁₋₃alkyl radical. As used herein, the term “C₁₋₆alkyl-cycloalkyl” indicates one or more cycloalkyl groups appended to a C₁₋₆ alkyl radical. The term “C₁₋₆alkylC₃₋₇cycloalkyl” indicates that the C₁₋₆alkyl is substituted by one or more saturated cyclic hydrocarbon (cycloalkyl) with 3, 4, 5, 6, 7 ring atoms. Examples are cyclopropylmethyl, cyclopropyl-ethyl, 3-cyclopropylpropyl, cyclopentyl-methyl, cyclobutylmethyl, and so on. The term “C₁₋₆alkylheterocycloalkyl” indicates that the C₁₋₆alkyl is substituted by one or more saturated heterocycle, as for example N-morpholin-3-ylmethyl, pyrrolidinylmethyl, N-piperidin-4-ylmethyl and 3-morpholinopropyl.

As used herein, the expression “C₁₋₆alkyl-N(R₇)₂” refers to a C₁₋₆alkyl as defined above wherein any one hydrogen is substituted by N(R₇)₂. Preferably, said “C₁₋₆alkyl-N(R₇)₂” is a “C₁₋₃alkyl-N(R₇)₂”, thus encompasses an alkyl of 1, 2 or 3 carbon atoms.

The term “spiro-C₃₋₈cycloalkyl” indicates a C₃₋₈cycloalkyl forming a bicyclic organic compound with rings connected through just one atom. The rings can be different in nature or identical. The connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Said spiro-C₃₋₈cycloalkyl ring may optionally contain a heteroatom and is also defined as a “spiro-C₃₋₈heterocycloalkyl”.

Included in the instant invention is the free base of compounds of Formula (I) or Formula (II) as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some of the specific compounds exemplified herein are the protonated salts of amine compounds. Compounds of Formula (I), (IA) or (IB) containing one or more N atoms may be protonated on any one, some or all of the N atoms. The term “free base” refers to the amine compounds in non-salt form. The encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula (I), (IA) or (IB). The free form of the specific salt compounds described may be isolated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base. In a preferred embodiment, the compounds of the invention have at least one acidic proton and the corresponding sodium or potassium salt can be formed, for example, by reaction with the appropriate base.

Thus, pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic or organic acid or an acid compound with an inorganic or organic base. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Conventional non-toxic salts further include those derived from an inorganic base, such as potassium, sodium hydroxide, magnesium or calcium hydroxide, as well as salts prepared from organic bases, such as ethylene diamine, lysine, tromethamine, meglumine and the like. Preferably, a pharmaceutically acceptable salt of this invention contains one equivalent of a compound of Formula (I), (IA) or (IB) and 1, 2 or 3 equivalent of an inorganic or organic acid or base. More particularly, pharmaceutically acceptable salts of this invention are the tartrate, trifluoroacetate or the chloride salts.

When the compound of the present invention is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.

It will also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.

Preferably, compounds of the present invention, including salts, tautomers, stereoisomers and solvates thereof, are SHP2 inhibitors, meaning that for example they can inhibit the activity or function of SHP2. Then, the present invention relates to compounds for use as inhibitors of at least one SHP2 function and to a method of inhibiting at least one SHP2 function comprising the step of contacting SHP2 with a compound as described herein.

“SHP2” means “Src Homology-2-phosphatase” and is also known as SH-PTP2, SH-PTP3, Syp, PTPID, PTP2C, SAP-2 or PTPN11.

The functions of SHP2 are varied as SHP2 is involved in multiple signaling processes, such as RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways. SHP2 regulates cancer cell survival and proliferation primarily by activating the RAS-ERK signaling pathway (T. Matozaki, Y. Murata, Y. Saito, H. Okazawa, H. Ohnishi, Cancer Sci, 100 (2009), pp. 1786-1793). In the RAS-ERK pathway, SHP2 acts as a positive regulator at upstream to promote RAS-RAF-ERK kinase cascade signaling transduction. Therefore, SHP2 inhibition leads to dephosphorylation of ERK and suppression of the pro-oncogenic function of RAS-RAF-ERK pathway, resulting in cell growth inhibition and apoptosis induction in cancer cells. Recently, Chen et al. (Y. N. Chen, M. J. LaMarche, H. M. Chan, P. Fekkes, J. Garcia-Fortanet, M. G. Acker, et al., Nature, 535 (2016), pp. 148-152) found that cancer cell lines sensitive to SHP2 depletion were also sensitive to EGFR depletion, which validated reports that RTK-driven cancer cells depend on SHP2 for survival. Furthermore, recent studies have shown that SHP2 is required for the growth of mutant KRAS-driven cancers while wild-type KRAS-amplified gastroesophageal cancer can be controlled through combined SHP2 and MEK inhibition (S. Mainardi, A. Mulero-Sanchez, A. Prahallad, G. Germano, A. Bosma, P. Krimpenfort, et al. Nat Med, 24 (2018), pp. 961-9; D. A. Ruess, G. J. Heynen, K. J. Ciecielski, J. Ai, A. Berninger, D. Kabacaoglu, et al. Nat Med, 24 (2018), pp. 954-960; G. S. Wong, J. Zhou, J. B. Liu, Z. Wu, X. Xu, T. Li, et al. Nat Med, 24 (2018), pp. 968-977). As a downstream target of several receptors, SHP2 is also involved in signaling in T-cells (M. Tajan, A. de Rocca Serra, P. Valet, T. Edouard, A. Yart, Eur J Med Genet, 58 (2015), pp. 509-525; R. J. Salmond, D. R. Alexander, Trends Immunol, 27 (2006), pp. 154-160). It is a downstream molecule in the PD-1 signaling pathway which not only suppresses T-cell activation but also causes T-cell anergy. SHP2-deficiency in T-cells triggered an anti-tumor immune response against colitis-associated cancer in mice (W. Liu, W. Guo, L. Shen, Z. Chen, Q. Luo, X. Luo, et al. Oncotarget, 8 (2017), pp. 7586-7597). Therefore, targeting SHP2 may restore or even enhance T-cell functions.

SHP2 inhibition may be assessed or measured by: the cell phenotype (as for example the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition, the mesenchymal phenotype in BTBC cells), cell proliferation, activity of SHP2, change in biochemical output produced by active SHP2, expression of SHP2, or binding of SHP2 with a natural binding partner may be monitored as a measure of SHP2 inhibition. In particular, inhibition of SHP2 activity or function can be measured by the IC₅₀ (concentration of inhibitor which reduces the activity of SHP2 to half-maximal level), as described in the assays hereinbelow or in the biochemical assays for SHP2 inhibition reported for example by Chen et al., Nature (535) 2016 or by Bagdanoff et al., J. Med. Chem. 2019, 62, 1781-1792. Preferably, compounds of the invention exhibit an IC₅₀ towards SHP2 lower than or equal to 10 μM. Preferred compounds exhibit an enzymatic IC₅₀ towards SHP2, as defined hereinbelow, lower than or equal to 3 μM (preferably lower than or equal to 0.5 μM or between 0.5 μM and 3 μM) and/or inhibition of SHP2 in cell based assays, as defined hereinbelow, with IC₅₀ lower than or equal to 5 μM (preferably lower than or equal to 1 μM or between 1 μM and 5 μM). Then, the compounds of the present invention, including salts, tautomers, stereoisomers and solvates thereof, may be for use in a method of inhibiting SHP2 activity. In other words, they may be for use in the prevention and/or treatment of any condition that would be ameliorated by SIP2 inhibition.

In a preferred embodiment, the compound or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above is for use in inhibiting SHP2 activity. Inhibition of SIP2 activity may be measured with respect to a proper control, such as a subject affected by a disease or disorder mediated by the activity of SIP2 or a subject throughout the course of a therapy for a disease or disorder mediated by the activity of SHP2. Preferably, compounds of the invention inhibit SHP2 activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% in respect to a proper control. More preferably, compounds of the invention inhibit SHP2 activity by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% in respect to a proper control. Yet more preferably, compounds of the invention inhibit SHP2 activity by more than 90%, for instance by approximately 92%, 94%, 95%, 98%, 99% or 100% in respect to a proper control.

Therefore, the compounds of the invention can be used for the treatment of diseases and for carrying out biological assays, cellular assays, biochemical assays or the like.

It is an object of the invention a compound or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above for medical use.

Preferably, the compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above is for use in inhibiting SHP2 activity. Inhibition of SHP2 activity further leads to dephosphorylation of ERK and suppression of the pro-oncogenic function of RAS-RAF-ERK pathway. Then, inhibition of SHP2 activity may be measured by ERK dephosphorylation, wherein ERK phosphorylation may be evaluated by any method known in the art, for instance as described in the Examples below. Dephosphorylation of ERK may be measured with reference to any proper control.

More preferably, the compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above is for use in the treatment and/or prevention of a disease or disorder mediated by the activity of SHP2. Preferably, the disease or disorder mediated by the activity of SHP2 is selected from the group consisting of: cancer, cardiovascular disease, immunological disorder, fibrosis, an ocular disorder, systemic lupus erythematosus, diabetes, neutropenia, and combinations thereof. Yet preferably, the disease or disorder mediated by the activity of SHP2 is selected from the group consisting of: Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and combinations thereof. Preferably any one of said cancers is a primary cancer or a cancer metastasis.

A disease or disorder mediated by the activity of SHP2 indicates a condition in a subject in which modulation, in particular inhibition, of SHP2 activity can prevent, inhibit, ameliorate, slow down or eradicate the condition and/or the symptomology thereof. Treatment of said disease or disorder might comprise administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) according to the invention.

In diseases or disorders mediated by the activity of SHP2, mutations are often observed at the N—SH2/PTP interface (e.g. E76D/E76K), resulting in constitutively active protein and abnormal proliferation. Cancers harboring “PTPN11 mutations” include but are not limited to: N58Y; D61Y, V; E69K; A72V, T, D; E76G, Q, K (ALL); G60A; D61Y; E69V; F71K; A72V; T73I; E76G, K; R289G; G503V (AML); G60R, D61Y, V, N; Y62D; E69K; A72T, V; T73I; E76K, V, G, A, Q; E139D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; A72V; E76A (MDS); Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (Lung cancer); R138Q (melanoma); E76G (colon cancer). The compounds of the invention can exhibit affinity at low concentrations for wild type SHP2 and can also be active against mutant forms of the protein.

Another aspect of the present invention relates to a compound of the invention, including any pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, as defined hereinabove for use in a method of preventing/treating an SHP2-mediated disorder and/or disorders mediated by the pro-oncogenic function of RAS-RAF-ERK pathway.

Another aspect of the present invention relates to a method of preventing/treating an SHP2-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, including any pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, as defined hereinabove. In another aspect, the present invention relates to a method of preventing/treating an SHP2-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of a chemotherapeutic agent, as further defined below, in combination with a therapeutically effective amount of a compound of the invention.

Another aspect of the present invention relates to the use of compounds of the invention, including any pharmaceutically acceptable salts tautomer, solvate or stereoisomer thereof, as defined hereinabove in preventing/treating an SHP2-mediated disorder.

In yet another aspect of the present invention, there are provided the compound, salt, solvate, stereoisomer or tautomer as defined above for use in the treatment and/or prevention of a disease or disorder selected from the group consisting of: cancer, cardiovascular disease, immunological disorder, fibrosis, an ocular disorder, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof. Preferably, the disease or disorder is selected from the group consisting of: Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and combinations thereof. Preferably, the cancer is a primary cancer or a cancer metastasis.

In certain embodiments the present invention relates to the aforementioned use/method, wherein said disorder is selected from Noonan Syndrome (NS) and Leopard Syndrome (LS).

In further embodiments, the present invention relates to the aforementioned use/method, wherein said SHP2-mediated disorders are those due to dysregulated cellular proliferation, including cancer. The cancer may be hormone-dependent or hormone-resistant, such as in the case of breast cancers. Preferably, the cancer is RTK-driven or KRAS-driven, such as KRAS amplified gastroesophageal cancer. In certain embodiments, the cancer is a solid tumor. In other embodiments, the cancer is a lymphoma or leukemia or a glioma. In certain embodiments, the cancer is a drug resistant phenotype of a cancer disclosed herein or known in the art. The cancer may be primary or metastatic. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis may also be treated using the compositions and methods disclosed herein. Precancerous neoplasias may also be treated using the compositions and methods disclosed herein.

Compounds of the invention can be used for the treatment of cancers selected from, but not limited to: Juvenile Myelomonocytic Leukemias (JMML); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); B cell acute lymphoblastic leukemia (B-ALL); neuroblastoma; esophageal; breast cancer; lung cancer; colon cancer; gastric cancer, head and neck cancer; ovarian cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), stomach, small intestine, large intestine, colon, rectum, liver and biliary passages; pancreas, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); gastroesophageal cancer (preferably KRAS-amplified gastroesophageal cancer), cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma and hematopoietic malignancies including leukemias Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), and lymphomas including lymphocytic, granulocytic and monocytic. Additional types of cancers which may be treated using the compounds and methods of the invention include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lymphomas, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myelomas, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, Wilm's tumor, anaplastic large-cell lymphoma, colitis associated cancer.

The compounds of the present invention may be useful in the treatment of any other disease or condition related to the aberrant activity of SHP2. Thus, as a further aspect, the invention relates to a method of treatment of a disorder selected from: NS; LS; JMML; AML; MDS; B-ALL; neuroblastoma; esophageal; breast cancer; lung cancer; colon cancer; gastric cancer; head and neck cancer.

A compound of the present invention, including any pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, may be usefully combined with any another known therapy that is useful for the prevention/treatment of a disease or disorder mediated by the activity of SHP2. Such therapy may include radiotherapy. Such therapy may also comprise the administration of another pharmacologically active compound, or of two or more other pharmacologically active compounds, particularly compound(s) active in the prevention/treatment of cancer, also referred to as “anti-cancer drug(s)” or “chemotherapy agents”. For example, a compound of the invention, including any pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above, may be administered simultaneously, sequentially or separately in combination with any one or more other pharmacologically active compound. For simultaneous administration, the compound of the present invention and the other one or more pharmacologically active compound may be formulated in the same composition.

Classes of anti-cancer drugs that may be combined with the compounds of the invention include, but are not limited to: alkylating agents, anti-metabolites, antimitotics, checkpoint inhibitors, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, anti-steroids and anti-androgens, mTOR inhibitors, tyrosine kinase inhibitors, and others. Chemotherapy agents include, for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine. Such combinations may offer significant advantages, including synergistic activity, in therapy.

Alkylating agents are compounds that work by adding an alkyl group to the guanine base of the DNA molecule, preventing the strands of the double helix from linking as they should thus causing breakage of the DNA strands and affecting the ability of the cancer cells to multiply.

Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. An antimitotic agent is a type of drug that blocks cell growth by stopping mitosis. Checkpoint inhibitors are a type of immunotherapy which block proteins that stop the immune system from attacking the cancer cells. Topoisomerase inhibitors are chemical compounds that block the action of topoisomerase (topoisomerase I and II), which is a type of enzyme that controls the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Aromatase inhibitors are a class of drugs that work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. Angiogenesis inhibitors are substances that inhibit the growth of new blood vessels and are used to treat cancers and other diseases that involve a proliferation of blood vessels. mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs (rapamycin and its analogs), which have shown tumor responses in clinical trials against various tumor types.

It is thus a preferred object of the invention a compound as defined above or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, for use in combination with at least one further therapeutic agent.

In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously.

Preferably, said at least one further therapeutic agent is selected from the group consisting of:

(a) alkylating agents, including but not limited to carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN); (b) anti-metabolites, including but not limited to cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX) and raltitrexed; (c) antimitotics, which are often plant alkaloids and terpenoids, or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunine; (d) checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors that target LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumour necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3) and/or OX40 (tumour necrosis factor receptor superfamily member 4); (e) topoisomerase inhibitors, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON) and etoposide (EPOSIN); (f) cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR) and exemestane (AROMASIN); (g) angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN); (h) anti-steroids and anti-androgens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) and nilutamide (NILANDRON); (i) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatininb (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; (12) monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) other agents, such as amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p′-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione and combinations thereof.

The invention further provides pharmaceutical preparations comprising the compounds of the invention. In particular, it is a further object of the invention a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above, alone or in combination with at least one further therapeutic agent, and at least one pharmaceutically acceptable excipient. Preferably, said at least one further therapeutic agent in the pharmaceutical composition is selected among those indicated above.

In a preferred embodiment, the pharmaceutical combination or the composition of the invention is for use in the treatment and/or prevention of a disease or disorder as herein defined, in particular a disease or disorder mediated by the activity of SHP2 and/or a disease or disorder selected from the group consisting of: cancer, cardiovascular disease, immunological disorder, fibrosis, an ocular disorder, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions of the invention may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water-soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.

The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.

The injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound(s) of the invention are employed. For purposes of this application, topical application shall include mouth washes and gargles.

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

The compounds of the invention may be presented in a liposome or other micro particulate or other nanoparticle designed to target the compound. Acceptable liposomes can be neutral, negatively, or positively charged, the charge being a function of the charge of the liposome components and pH of the liposome solution. Liposomes can be normally prepared using a mixture of Phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphotidylglycerol, phosphatidylinositol. Polyethylene glycol can be added to improve the blood circulation time of liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms. Generally, dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kg of body weight are useful in the treatment of the above indicated conditions.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Another object of the present invention relates to an in vitro method of inhibiting SHP2 with the compound of the present invention. This may be useful, for instance, to evaluate whether any given compound is an inhibitor/activator of SHP2 and therefore acts also on the ERK pathway.

A further object of the present invention concerns a kit comprising at least one pharmaceutically acceptable vial or container of other type, containing one or more doses of a compound of the invention, including any pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, or of a pharmaceutical composition of the invention and optionally a) instructions for use thereof in mammals and/or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

In certain embodiments, the compound or the composition of the invention is administered parenterally, intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically, intranasally, or systemically.

In certain embodiments, the patient who is administered the compound or the composition of the invention is a mammal, preferably a primate, more preferably a human.

The compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

As used herein, the term “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. As used herein, any reference to “treatment”/“treating” includes the amelioration of at least one symptom of the disease/disorder to be treated. Such amelioration is to be evaluated in comparison to the same symptom prior to administration of the compound or composition of the invention.

The term “therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The present invention will be described by means of the following non-limiting examples and biological data.

MATERIALS AND METHODS Chemistry

As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

Abbreviations

AcOH: Acetic acid; (Boc)₂O: Di-tert-butyl dicarbonate; CDI 1,1′-Carbonyldiimidazole; DCM:Dichloromethane; DIPEA: N,N-Diisopropylethylamine; DMA: N,N-Dimethylacetamide; DMAP:4-(Dimethylamino)pyridine; DMSO: Dimethylsulfoxide; ES⁺: Electrospray Positive Ionisation; EtOAc: Ethyl acetate; EtOH: Ethanol; h: Hour; H₂O: Water; HPLC: High Performance Liquid Chromatography; LCMS: Liquid Chromatography Mass Spectrometry; mCPBA: meta-Chloroperoxybenzoic acid; MeCN: Acetonitrile; Mel: Iodomethane; MeOH: Methanol; min: Minute; MW: Microwave; Na₂CO₃: Sodium carbonate; NaHCO₃: Sodium bicarbonate; Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium(O); POCl₃: Phosphoryl chloride; Pd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium(O); RP: Reverse Phase; RT: Retention time; rt: Room temperature; SEM: trimethylsilylethoxymethyl; TCDI: 1-1′-Thiocarbonyldiimidazole; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; Sat.: Saturated; Sol.: Solution; UPLC: Ultra High Performance Liquid Chromatography; Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

General

Solvents and reagents were obtained from commercial suppliers and were used without further purification. Flash chromatography purifications were performed on prepacked cartridges on a Biotage system. Purity of final compounds was determined using MS and UPLC. UPLC-MS analyses were performed on a Waters Acquity UPLC™, equipped with a diode array and a ZQ mass spectrometer, using an X-Terra C18 column (5 m, 4.6×50 mm) or a BEH C18 column (1.7 mm, 2.1×50 mm). Mobile phase comprised a linear gradient of binary mixtures of H₂O containing 0.1% formic acid (A), and MeCN containing 0.1% formic acid (B). The linear gradient used is: (A): 90% (0.1 min), 90%-0% (2.6 min), 0% (0.3 min), 0%-90% (0.1 min) with a 0.5 mL/min flow. Purity of final compounds was >95%. All ¹H spectra were recorded on Bruker AV400 spectrometer at 400 MHz except where indicated. Chemical shift (6) are reported in parts per million relative to TMS using CDCl₃ as a solvent or relative to the residual solvent signal using DMSO-d₆. Coupling constants (J) are reported in Hertz (Hz). Multiplicities are reported as singlet (s), broad (br), doublet (d), doublet of doublet (dd), doublet of doublet of doublet (ddd), triplet (t), doublet of triplet (dt), doublet of doublet of triplet (ddt), triplet of triplet (tt), quartet (q), doublet of quartets (dq) or multiplet (m). Unless indicated, spectra were acquired at 300 K. Temperatures are expressed in degrees Celsius (° C.) and are uncorrected.

Processes for Making the Compounds of the Invention

The present invention also includes processes for the preparation of compounds of the invention. The following schemes are examples of synthetic routes that may be adopted to prepare compounds of the invention.

In the reaction schemes described below, it can be useful to protect reactive functional groups, for example amino, imino, hydroxyl, thio or carboxy groups, to avoid their unwanted participations to reactions. Conventional protecting groups can be used in accordance with standard practice, for example see T. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991.

Those skilled in the art will readily appreciate that certain compounds of the invention can be converted into other compounds of the invention according to standard chemical methods (e.g. by salification/desalification).

Compounds of Formula (I) can be prepared according to the following Reaction Schemes A-D, wherein all substituents are as defined above.

According to Reaction Scheme A, compounds of formula (I) are prepared by reacting the bromine derivative (A) with the appropriate R₄ nucleophilic derivative (including, for example, an aryl or heteroaryl thiol or the corresponding thiolate salt, or an amino derivative, or an hydroxyl-derivative) in the presence of the suitable catalyst (such as a palladium or copper catalyst) and a buffering base. In the absence of a catalyst, the reaction can also be carried out under photochemical conditions. It is to be understood that other leaving groups could be used instead of bromine.

Compounds of Formula (I), wherein Y is S can also be prepared according to the following Reaction Scheme B.

In reaction Scheme B, the bromine on compound (A) is first converted into a thioether derivative in the presence of Palladium catalyst and then further cross-coupled with an aryl derivative of formula R₄X still in the presence of a suitable Pd catalyst and a base. 2-Ethylhexyl 3-mercaptopropionate is shown in the example, but other hydrogen sulfide surrogates could also be used.

Compounds of Formula (I) wherein Y is a bond can be prepared according to the Reaction Scheme C, wherein the bromine on compound (A) is coupled with the appropriate R₄-boronic acid (or boronate) derivative in the presence of a suitable palladium catalyst.

It is to be understood that other leaving groups could be used instead of bromine.

Compounds of Formula (I) can also be prepared according to the Reaction Scheme D:

According to Reaction Scheme D, the compound of Formula (I) is obtained by displacing a leaving group, such as halogen, SO₂Me or SOMe, with an amine in the presence of a further suitable base. In the above reaction strategies, when X₁, or X₂ is NH the nitrogen can be protected, for instance as the corresponding trimethylsilylethoxymethyl (SEM) derivative. The reactions above proceed at a temperature ranging from room temperature to about 140° C.

Compounds of Formula (I) can also be modified by appending the appropriate functionalities to enhance selective biological properties. For example, the synthesis of compounds of Formula (I) may include an alkylation step of a NH group, the methylation or the halogenation of the aromatic or heteroaromatic structure, or the preparation of the N-oxide of a pyridine derivative. Said modifications are included in the detailed examples of synthesis of compounds of Formula (I).

Detailed examples of the synthesis of compounds of Formula (I) and of Formula (II) can be found in the Schemes and in the Examples below.

Unless otherwise indicated, all starting materials reported in this experimental section have been previously described in literature or are commercially available. The indication of the commercial source of certain compounds in the description of the experimental procedure, when provided, is only for easy reference to skilled chemist and should not be interpreted as the indication to use only that particular commercial compound. (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, (S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine, (R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide, tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate tert-butyl (4S)-4-((tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate were prepared according to the procedures indicated in WO2018/172984; (S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, (S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, (S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, (S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, 2-methyl-N—((R)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)propane-2-sulfinamide, N—((S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, N—((S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, N—((S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, N—((S)-5-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide, N—((S)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide were prepared according to WO2019/183367; N—((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, N—((S)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, N—((S)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide were prepared according to WO2020/094104; (S)-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine was prepared according to WO2020/063760; 2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide was prepared according to WO2018/218133.

The following examples were synthesized using according to the Schemes and the procedures described infra or modifications thereof using the appropriate starting materials (Table 1).

TABLE 1 Compounds prepared according to the Examples and experimental data (MS). MS Ex Structure IUPAC Name [M + H]⁺  1

4-methyl-1-(6-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 410  2

(R)-8-(6-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-8- azaspiro[4.5]decan-1-amine 450  3

(R)-8-(6-((2,3-dichlorophenyl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-8- azaspiro[4.5]decan-1-amine 449  4

4-methyl-1-(1-methyl-6-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 424  5

2-(1,7-diazaspiro[3.5]nonan-7-yl)-5- ((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazine 422  6

4-methyl-1-(6-((1-methyl-1H- indazol-5-yl)thio)-1H-imidazo[4,5- b]pyrazin-2-yl)piperidin-4-amine 395  7

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 396  8

(1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-yl)methanamine 410  9

4-methyl-1-(6-(thieno[2,3-c]pyridin- 3-ylthio)-1H-imidazo[4,5-b]pyrazin- 2-yl)piperidin-4-amine 398  10

2-(4-((2-(4-amino-4-methylpiperidin- 1-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)thio)phenyl)-2,4-dihydro-3H- 1,2,4-triazol-3-one 424  11

4-methyl-1-(6-(phenylthio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 341  12

4-methyl-1-(6-(pyridin-3-ylthio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 342  13

1-(1-(cyclopropylmethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 464  14

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)pyrrolidin-3-amine 382  15

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)azetidin-3-amine 368  16

N-methyl-1-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 410  17

2-(2,6-diazaspiro[3.5]nonan-2-yl)-5- ((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazine 422  18

4-methyl-1-(5-((2- (trifluoromethyl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 409  19

4-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3- (trifluoromethyl)benzonitrile 434  20

1-(5-((2,4-difluorophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 377  21

1-(5-((2,3-difluorophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 377  22

1-(5-((2,3-dichlorophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 409  23

2-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)benzonitrile 366  24

1-(5-((2-methoxyphenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 371  25

1-(5-((3-methoxyphenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 371  26

3-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)benzonitrile 366  27

4-methyl-1-(5-((4- (trifluoromethoxy)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 425  28

1-(5-((3-chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 376  29

1-(4-((2-(4-amino-4-methylpiperidin- 1-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)thio)phenyl)cyclobutane-1- carbonitrile 420  30

1-(6-(benzo[b]thiophen-3-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 397  31

2-(piperidin-1-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazine 381  32

N-((1H-pyrazol-5-yl)methyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 393  33

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-3-amine 396  34

N-(piperidin-4-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 396  35

(R)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 481  36

1-(5-((2-chloro-5- (trifluoromethyl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 443  37

1-(5-((2-bromophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 419  38

1-(5-((4-chloro-2- methylphenyl)thio)-1H-imidazo[4,5- b]pyrazin-2-yl)-4-methylpiperidin-4- amine 389  39

1-(5-((2,3-dimethylphenyl)thio)-1H- imidazo [4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 369  40

N-(1-(5-((2-(trifluoromethyl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)piperidin-4- yl)methanesulfonamide 474  41

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-ol 397  42

2-(4-((1H-imidazol-1- yl)methyl)piperidin-1-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazine 461  43

N-(2-(imidazo[1,2-a]pyridin-2- yl)ethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 457  44

2-(1,7-diazaspiro[3.5]nonan-1-yl)-5- ((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazine 422  45

1-(5-((4-methoxyphenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 371  46

1-(5-((3-cyclopropylphenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 381  47

4-methyl-1-(5-((6- (trifluoromethyl)pyridin-2-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 410  48

4-methyl-1-(5-((3-(2-methylthiazol- 4-yl)phenyl)thio)-1H-imidazo[4,5- b]pyrazin-2-yl)piperidin-4-amine 438  49

4-methyl-1-(6-(quinolin-5-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 392  50

N-(2H-indazol-5-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 429  51

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidine-4-carboxamide 424  52

4-methyl-1-(1-methyl-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 424  53

2-(4-(1-methyl-1H-imidazol-4- yl)piperidin-1-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazine 461  54

N1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)butane-1,3-diamine 384  55

(1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)azetidin-3-yl)methanamine 382  56

2-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)octahydro-2H-pyrazino[1,2- a]pyrazine 437  57

4-methyl-1-(5-((5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3- yl)thiophen-2-yl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 495  58

1-(5-([1,1′-biphenyl]-3-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 417  59

4-methyl-1-(5-((4-(5-phenyl-1,3,4- oxadiazol-2-yl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 485  60

4-methyl-1-(5-(naphthalen-1-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 391  61

4-methyl-1-(5-(quinolin-4-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 392  62

1-(5-((1,5-naphthyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 393  63

1-(1-ethyl-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 438  64

1-(5-((2-bromopyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 420  65

4-methyl-1-(5-(pyrazolo[1,5- a]pyrimidin-5-ylthio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 382  66

6-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)pyridin-2-ol 358  67

4-methyl-1-(5-((4-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 412  68

4-methyl-1-(5-((3-methylthiophen-2- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 361  69

1-(5-((6-methoxyquinolin-2-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 422  70

1-(5-(isoquinolin-5-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 392  71

4-methyl-1-(5-(quinoxalin-5-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 393  72

1-(1-ethyl-6-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 438  73

1-(5-((2-chlorothiophen-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 381  74

4-methyl-1-(5-((2-(pentafluoro-l6- sulfaneyl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 467  75

4-methyl-1-(5-((2-(2-methylprop-1- en-1-yl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 395  76

7-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-2,3-dihydro-1H-inden-1-one 395  77

1-(5-((1,3-dihydroisobenzofuran-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-4-methylpiperidin-4-amine 383  78

methyl 2-((2-(4-amino-4- methylpiperidin-1-yl)-1H- imidazo[4,5-b]pyrazin-5- yl)thio)benzoate 399  79

2-(4-(5-((2-(trifluoromethyl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,4-diazepan-1-yl)ethan-1-ol 440  80

4-methyl-1-(5-(pyridin-4-ylthio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 342  81

4-methyl-1-(5-(naphthalen-2-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 391  82

2-(4-(((5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)amino)methyl)piperidin-1- yl)ethan-1-ol 454  83

7-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1-oxa-3,7-diazaspiro[4.5]decan- 2-one 452  84

N-(2-azaspiro[3.3]heptan-6-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 408  85

1-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)azepan-4-amine 410  86

1-(4-(5-((2-(trifluoromethyl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)morpholin-2-yl)ethan-1-amine 426  87

N-(2-methyl-2-morpholinopropyl)-5- ((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- amine 454  88

4-methyl-1-(5-(quinolin-8-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 392  89

N-(2-(piperidin-2-yl)ethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 424  90

(1S,4S)-2-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-2,5- diazabicyclo[2.2.2]octane 408  91

2-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)quinazolin-4(3H)-one 409  92

1-(5-(isoquinolin-8-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 392  93

4-methyl-1-(5-((3-(pentafluoro-l6- sulfaneyl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 467  94

3-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)benzoic acid 385  95

4-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)benzoic acid 385  96

(3S,4S)-3-methyl-8-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-2- oxa-8-azaspiro[4.5]decan-4-amine 466  97

4-methyl-1-(5-((8- trifluoromethyl)quinolin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 460  98

1-(5-((2-chlorophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 375  99

4-((2-(4-amino-4-methylpiperidin-1- yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3-chlorobenzoic acid 419 100

4-methyl-1-(5-(quinazolin-5-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 393 101

4-methyl-1-(5-(quinazolin-4-ylthio)- 1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 393 102

4-methyl-1-(5-((2-(thiazol-2- yl)phenyl)thio)-1H-imidazo[4,5- b]pyrazin-2-yl)piperidin-4-amine 424 103

2-(3-((2-(4-amino-4-methylpiperidin- 1-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)phenyl)acetic acid 399 104

4-methyl-1-(5-(pyrazolo[1,5- a]pyrimidin-7-ylthio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 382 105

1-(5-((1,8-naphthyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 393 106

4-methyl-1-(5-((2-methylquinolin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 406 107

(S)-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 498 108

6-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,6,7,8-tetrahydro-1,6- naphthyridin-3-amine 445 109

N6-(5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-8-oxabicyclo[3.2.1]octane-2,6- diamine 438 110

N-(piperidin-4-ylmethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 410 111

N-(morpholin-3-ylmethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 412 112

N-((2-morpholinopyridin-3- yl)methyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 489 113

N-(2,2-dimethyl-3-(pyridin-3- yl)propyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 460 114

1-(5-((3-chloro-2- methylphenyl)thio)-1H-imidazo[4,5- b]pyrazin-2-yl)-4-methylpiperidin-4- amine 389 115

1-(5-((2-isopropylphenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 383 116

1-((5-((1H-benzo[d]imidazol-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-4-methylpiperidin-4-amine 381 117

4-methyl-1-(5-((2- (methylsulfonyl)phenyl)thio)-1H- imidazo[4,5-b]pyrazin-2- yl)piperidin-4-amine 419 118

(S)-1′-(6-chloro-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 532 119

4-methyl-1-(5-((2- (trifluoromethyl)pyridin-3- yl)thio)thiazolo[4,5-b]pyrazin-2- yl)piperidin-4-amine 427 120

(R)-8-(6-(3,4-dihydro-1,5- naphthyridin-1(2H)-yl)-1H- imidazo[4,5-b]pyrazin-2-yl)-8- azaspiro[4.5]decan-1-amine 405 121

2-(4-amino-4-methylpiperidin-1-yl)- N-(2,3-dichlorophenyl)-1H- imidazo[4,5-b]pyrazin-5-amine 392 122

1-(5-(2,3-dichlorophenoxy)-1H- imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 393 123

N-(3-morpholinopropyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 440 124

2-(9,9-dimethyl-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazine 450 125

2-(3,9-diazabicyclo[4.2.1]nonan-3- yl)-5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazine 422 126

N-(5-azaspiro[3.5]nonan-8-yl)-6-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-amine 436 127

(8-(6-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-8-azaspiro[4.5]decan-1- yl)methanamine 464 128

N-((5-phenylpyrrolidin-3-yl)methyl)- 5-((2-(trifluoromethyl)pyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- amine 472 129

1-(1-(2-methoxyethyl)-5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4- methylpiperidin-4-amine 468 130

(S)-1′-(6-((3-chloro-2- (methylamino)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 493 131

1-[5-(2,3-Dichlorophenyl)-1H- imidazo[4,5-b]pyrazin-2-yl]-4- methylpiperidin-4-amine 377 132

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 479 133

1-(5-((2,3-dichlorophenyl)thio)-6- methyl-1H-imidazo[4,5-b]pyrazin-2- yl)-4-methylpiperidin-4-amine 423 134

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3,3-difluoro-1- methylindolin-2-one 534 135

(S)-1-(4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3,3-difluoroindolin-1- yl)ethan-1-one 548 136

(S)-1′-(5-((2,2- difluorobenzo[d][1,3]dioxol-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 509 137

(S)-2-(2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-((2-(trifluoromethyl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 1-yl)acetamide 555 138

(S)-2-(2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-((2-(trifluoromethyl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 1-yl)ethan-1-ol 454 139

(S)-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 499 140

(S)-1′-(5-(3-chloro-2- (methylamino)pyridin-4-yl)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 461 141

(S)-3-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-2-(trifluoromethyl)pyridine 1-oxide 514 142

(S)-2-methyl-N-(1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-yl)propane-2- sulfonamide 619 143

(R)-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-3H- spiro[benzofuran-2,4′-piperidin]-3- amine 500 144

1-(2-((2,3-dichlorophenyl)thio)-7H- purin-8-yl)-4-methylpiperidin-4- amine 409 145

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 480 146

(S)-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 494 147

(S)-N-(4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3-chloropyridin-2- yl)acetamide 521 148

(S)-1′-(5-((3-chloropyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 464 149

(R)-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 498 150

(S)-1′-(5-((3-chloropyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5 -amine 465 151

(S)-1′-(5-((3-chloro-2- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 495 152

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3-chloropyridin-2-ol 480 153

(S)-1′-(5-((3-chloro-2-(oxetan-3- yloxy)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 537 154

(S)-1′-(5-((3-chloro-2- (dimethylamino)pyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 508 155

(R)-1′-(5-((3-chloropyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-3H- spiro[benzofuran-2,4′-piperidin]-3- amine 466 156

(S)-1′-(5-((4- (trifluoromethyl)pyrimidin-5-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1- amine 499 157

(S)-8-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-2H-benzo[b][1,4]oxazin- 3(4H)-one 500 158

(S)-1′-(5-((3-chloropyrazin-2-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1- amine 465 159

(R)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 481 160

(S)-1′-(5-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 519 161

(S)-1′-(6-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 520 162

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3,3-difluoroindolin-2-one 520 163

(R)-1′-(5-((3-chloropyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-3H-spiro[furo[3,2-b]pyridine- 2,4′-piperidin]-3-amine 467 164

(S)-1′-(6-((1,5-naphthyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 481 165

(S)-1-(4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3-chloropyridin-2- yl)azetidin-3-ol 535 166

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)thio)-3-chloro-1-methylpyridin- 2(1H)-one 494 167

(S)-1′-(6-((2,3- dihydrobenzo[b][1,4]dioxin-5- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 487 168

(S)-6-((2-(5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]- 1′-yl)-1H- imidazo[4,5-b]pyrazin-6-yl)thio)-4- chlorobenzo[d]oxazol-2(3H)-one 521 169

(S)-6-((2-(5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-1′-yl)-1H- imidazo[4,5-b]pyrazin-6-yl)thio)-5- chloro-2H-benzo[b][1,4]oxazin- 3(4H)-one 535 170

(S)-5-((2-(5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]- 1′-yl)-1H- imidazo[4,5-b]pyrazin-5-yl)thio)-3,4- dihydroquinolin-2(1H)-one 499 171

(S)-1′-(5-((2,3-dichloropyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 499 172

(S)-1′-(5-((2,3-dichlorophenyl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 498 173

(S)-8-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)thio)-4-methyl-2H- benzo[b][1,4]oxazin-3(4H)-one 514 174

(R)-1′-(5-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 521 175

(S)-1′-(6-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 497 176

(S)-1′-(6-(quinolin-4-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 480 177

(S)-1′-(6-((3-methoxypyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 460 178

(S)-7-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)thio)benzo[d]oxazol-2(3H)-one 486 179

(S)-1′-(5-(quinoxalin-5-ylthio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 481 180

(S)-1′-(5-((3-chloro-2- morpholinopyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 549 181

(S)-1′-(5-((3-chloro-2-(3- methoxyazetidin-1-yl)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 549 182

(S)-6-fluoro-1′-(6-((3- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 478 183

(S)-1′-(6-((3-chloropyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-6- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 482 184

(S)-1′-(6-((3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-6- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 504 185

(S)-1′-(6-((2-amino-5-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 479 186

(S)-1′-(6-((3-chloropyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-6- fluoro-5-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 512 187

(S)-6-fluoro-1′-(6-((3-fluoropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 466 188

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-5,6-difluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 515 189

(S)-1′-(5-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,6-difluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 555 190

(S)-1′-(6-((2-amino-3- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-6- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 493 191

(S)-1-(4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-3-chloropyridin-2- yl)azetidine-3-carbonitrile 544 192

(S)-6-fluoro-1′-(5-(imidazo[1,2- a]pyridin-8-ylthio)-1H-imidazo[4,5- b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 487 193

(S)-1′-(5-((1H-indol-6-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 468 194

(S)-1′-(6-(pyrido[2,3-b]pyrazin-8- ylthio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 482 195

(S)-1′-(6-((3-chloro-2-methylpyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 196

(S)-1′-(5-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,7- dihydrospiro[cyclopenta[c]pyridine- 6,4′-piperidin]-5-amine 520 197

(R)-1′-(5-((3-chloro-2- (cyclopropylamino)pyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-5,7- dihydrospiro[cyclopenta[c]pyridine- 6,4′-piperidin]-5-amine 520 198

(S)-1′-(6-((1H-indol-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 468 199

(S)-1′-(6-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-5-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 497 200

(S)-1′-(5-((3-ethoxypyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 474 201

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-2- (methylamino)nicotinonitrile 484 202

(S)-1′-(5-((2-methyl-2H-indazol-7- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 483 203

(S)-1′-(6-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-7-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 497 204

(S)-1′-(6-((2-amino-3-methylpyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 459 205

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 509 206

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-4-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 497 207

(S)-1′-(5-((3-chloropyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-4-fluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 482 208

(S)-1-amino-1′-(5-((2-amino-3- chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 6-ol 495 209

(R)-N-((S)-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 597 210

(S)-1′-(5-((3-aminopyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 445 211

(S)-1′-(5-((2- (dimethylamino)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 473 212

(S)-1′-(5-(thieno[3,2-b]pyridin-7- ylthio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 486 213

(S)-1′-(5-(benzo[c][1,2,5]oxadiazol- 4-ylthio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 471 214

(S)-1′-(5-((2-methoxypyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 460 215

(S)-2-amino-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)nicotinonitrile 470 216

(S)-5-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)quinoxalin-2(1H)-one 497 217

(S)-3-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)picolinonitrile 455 218

(S)-1′-(5-((5-fluoroquinolin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 498 219

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 558 220

(S)-1′-(5-((6-methoxy-1,5- naphthyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 511 221

(S)-3-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-4H-pyrido[1,2-a]pyrimidin- 4-one 497 222

(S)-1′-(5-((2-amino-3-fluoropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 463 223

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-morpholino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 564 224

(S)-3-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-N-methylpicolinamide 487 225

(S)-1′-(5-((2-(pyrrolidin-1-yl)pyridin- 3-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 499 226

(S)-1′-(5-((3- (trifluoromethoxy)pyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 514 227

(S)-1′-(5-((3-((2-methyloxazol-4- yl)methoxy)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 541 228

(S)-6-bromo-1′-(5-((3-chloro-2- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 573 229

(R)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-3-fluoro-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 498 230

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-3-fluoro-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 498 231

(S)-6-bromo-1′-(5-((2- methoxypyridin-3-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 538 232

(S)-1′-(5-((1H-pyrrolo[2,3-b]pyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 469 233

1′-(5-((2-amino-3-chloropyridin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-2-methyl-2,6-dihydro-4H- spiro[cyclopenta[c]pyrazole-5,4′- piperidin]-4-amine 483 234

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)pyridazin-3(2H)-one 447 235

(S)-1′-(5-((2-(oxazol-2- ylmethoxy)pyridin-3-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 527 236

(S)-1′-(5-((3-methoxypyridazin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 461 237

(S)-1′-(5-((4-methoxypyridin-3- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 460 238

(S)-3-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)pyridin-2(1H)-one 446 239

(S)-1′-(5-((3-chloro-2- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 494 240

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-1H-pyrrolo[2,3-b]pyridine-3- carbonitrile 494 241

(S)-4-((2-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-imidazo[4,5-b]pyrazin-5- yl)thio)-5-chloropyridin-2-ol 480 242

(S)-1′-(5-((5-chloro-2- methoxypyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 494 243

(S)-1′-(2-((2,3-dichlorophenyl)thio)- 5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 496 244

(S)-(1-amino-1′-(5-((2-amino-3- chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 6-yl)methanol 509 245

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-(fluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 511 246

(S)-1′-(5-((3-chloro-2- (ethylamino)pyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 507 247

(S)-1′-(5-((3-chloropyridazin-4- yl)thio)-1H-imidazo[4,5-b]pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 465 248

(S)-1′-(7-chloro-2-((2,3- dichlorophenyl)thio)-5H-pyrrolo[2,3- b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 531 249

(S)-1′-(5-(3,4-dihydro-1,5- naphthyridin-1(2H)-yl)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 453 250

(S)-1′-(5-((5-(aminomethyl)-2- methoxypyridin-3-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 489 251

(S)-1′-(5-((6-chloroimidazo[1,2- b]pyridazin-8-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 504 252

(S)-(1-amino-1′-(5-((2-amino-3- chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 5-yl)methanol 509 253

methyl (S)-6-(1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-2-((2,3-dichlorophenyl)thio)- 5H-pyrrolo[2,3-b]pyrazine-7- carboxylate 554 254

(S)-1′-(5-((8-methyl-1,5- naphthyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 495 255

(S)-1′-(5-((2-methyl-2H- pyrazolo[3,4-b]pyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 484 256

(S)-1-amino-1′-(5-((2-amino-3- chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]- 6-carbonitrile 504 257

(S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)-1H-imidazo[4,5-b]pyrazin- 2-yl)-6-cyclopropyl-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 519 258

(S)-2-chloro-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole- 5,4′-piperidin]-4-amine 539 259

(S)-1′-(6-chloro-5-((2,3- dichlorophenyl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 532 260

(R)-1-amino-1′-(5-((2-amino-3- chloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]- 6-carbonitrile 504 261

(S)-1′-(5-((1-methyl-1H- pyrazolo[4,3-b]pyridin-7-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 484 262

(S)-1′-(5-((2-chloro-3- (trifluoromethyl)pyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 533 263

(S)-1′-(5-((2- (trifluoromethyl)pyridin-3-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole- 5,4′-piperidin]-4-amine 505 264

(S)-1′(5-((2-(methylamino)-3- (trifluoromethyl)pyridin-4-yl)thio)- 1H-imidazo[4,5-b]pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 528 265

(S)-1′-(2-((2-amino-3-chloropyridin- 4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin- 6-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 478 266

(S)-1′-(5-((6-amino-2,3- dichloropyridin-4-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 513 267

(S)-1′-(2-((2-amino-3-chloropyridin- 4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin- 6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 479 268

(3S,4S)-8-(2-((2-amino-3- chloropyridin-4-yl)thio)-5H- pyrrolo[2,3-b]pyrazin-6-yl)-3- methyl-2-oxa-8-azaspiro[4.5]decan- 4-amine 446 269

(S)-1′-(5-((6-amino-2- methoxypyridin-3-yl)thio)-1H- imidazo[4,5-b]pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine 475

Exemplary and non-limiting processes for the synthesis of specific examples are reported hereinbelow.

Example 22: 1-[5-((2,3-Dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to the general scheme indicated below (Scheme 1), wherein R is 2-ethylhexyl, Ar is 2,3-dichlorophenyl and X is halide (bromine).

Scheme 1

Step 1: 5-Bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-thione (Intermediate 1)

A solution of 5-bromopyrazine-2,3-diamine (Sigma Aldrich, cat. No. 68573) (5.0 g, 26.5 mmol) in 1,4-dioxane (55 mL) was treated with thiocarbonyldiimidazole (TDCI; 6.6 g, 37.0 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the reaction mixture was concentrated in vacuo and purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound as a yellow solid (5.4 g, 79%). ¹H NMR (DMSO-d₆) δ 13.62 (br s, 2H), 8.22 (s, 1H). LCMS (ES⁺) m/z 231, 233 (M+H)⁺, RT 0.87 min.

Step 2: 6-Bromo-2-(methylthio)-1H-imidazo[4,5-b]pyrazine

A solution of 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-thione (Intermediate 1) (3.0 g, 13.0 mmol) in H₂O (85 mL) at rt was treated with NaOH (799 mg, 19.5 mmol) and stirred at this temperature until complete dissolution of the starting material. Then, iodomethane (1.2 mL, 19.5 mmol) was added and the reaction mixture was stirred at rt for 1 h. A solution of NaOH 2N was added until dissolution of the solid and the aqueous solution was washed with CHCl₃, concentrated and acidified to pH 6.5 with aqueous HCl 6 N. The resulting precipitate was filtered off and washed with H₂O to give the title compound as a pale yellow solid (1.8 g, 56%). ¹H NMR (DMSO-d₆) δ 7.76 (s, 1H), 2.55 (s, 3H). LCMS (ES⁺) m/z 245, 247 (M+H)⁺; RT 1.03 min.

Step 3: 6-Bromo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine

m-CPBA (4.2 g, 18.4 mmol) was added portionwise to a solution of 6-bromo-2-(methylthio)-1H-imidazo[4,5-b]pyrazine (1.8 g, 7.3 mmol) in DCM (70 mL) at 0° C., then the resulting reaction mixture was stirred at rt for 3 h. After addition of aqueous HCl 6 N (10 mL) the mixture was extracted with a solution of CHCl₃/EtOH 95:5 (3×150 mL). The organic phase was washed with H₂O and brine. The dried organics were concentrated in vacuo and the residue was purified on RP silica gel (eluting with 0-50% MeCN/H₂O (0.1% TFA) to give the title compound as a white solid (1.5 g, 75%). ¹H NMR (DMSO-d₆) δ 8.79 (s, 1H), 3.56 (s, 3H). LCMS (ES⁺) m/z 277, 279 (M+H)⁺; RT 0.86 min.

Step 4: tert-Butyl (1-[5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-yl)carbamate (Intermediate 2)

tert-Butyl N-(4-methylpiperidin-4-yl)carbamate (1.4 g, 6.6 mmol) and 6-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine (1.5 g, 5.5 mmol) were dissolved in 1,4-dioxane (40 mL) and the solution was heated at 100° C. for 4 h. After cooling, the mixture was concentrated in vacuo and purified on silica gel (eluting with 0-55% EtOAc/Petroleum ether) to give the title compound as a pale yellow solid (1.1 g, 46%). ¹H NMR (CDCl₃) δ 7.96 (s, 1H), 4.48 (br s, 1H), 3.99-3.96 (m, 2H), 3.59-3.56 (m, 2H), 2.28-2.25 (m, 2H), 1.75-1.73 (m, 2H), 1.46 (s, 9H), 1.43 (s, 3H). LCMS (ES⁺) m/z 411, 413 (M+H)⁺, RT 1.51 min.

Step 5: tert-Butyl (1-[5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl]-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 3)

NaH (21.4 mg, 0.5 mmol, 60% in mineral oil) was added portionwise to a solution of tert-butyl (1-[5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-yl)carbamate (Intermediate 2; 200 mg, 0.5 mmol) in DMF (4.5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h, then 2-(chloromethoxy)ethyl-trimethylsilane (125 μL, 0.6 mmol) was added dropwise and the mixture was stirred at rt for 30 min. After carefully addition of H₂O (2 mL) the mixture was extracted with DCM. The organic extracts were washed with H₂O and brine. The dried organics were concentrated in vacuo and the residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound (1:1 mixture of regioisomers) as a white solid (160 mg, 61%). ¹H NMR (DMSO-d₆) δ 8.24 (s, 1H), 8.04 (s, 1H), 6.69 (br s, 2H), 5.38 (d, J=12.3 Hz, 4H), 3.95-3.92 (m, 4H), 3.75-3.72 (m, 4H), 3.48-3.45 (m, 4H), 2.19-2.16 (m, 4H), 1.59-1.56 (m, 4H), 1.40 (s, 18H), 1.27 (s, 6H), 0.93-0.90 (m, 4H), −0.04 (s, 18H). LCMS (ES⁺) m/z 541, 543 (M+H)⁺, RT 2.61 and 2.63 min.

Step 6: 2-Ethylhexyl 3-[(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl]-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-imidazo[4,5-b]pyrazin-5-yl)thio)propanoate (Intermediate 4)

tert-Butyl (1-[5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-yl)carbamate (Intermediate 3; 855 mg, 1.6 mmol), 2-ethylhexyl 3-mercaptopropanoate (718 μL, 3.2 mmol), DIPEA (550 μL, 3.12 mmol), Pd₂(dba)₃ (72 mg, 0.08 mmol) and Xantphos (91 mg, 0.16 mmol) were dissolved in 1,4-dioxane (16 mL) and the reaction mixture was heated at 110° C. for 1 h. After cooling, the mixture was filtered through a pad of Solka Floc and washed with EtOAc. The organic phase was concentrated in vacuo and the residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound (1:1 mixture of regioisomers) as a yellow oil (1.06 g, 99%). ¹H NMR (DMSO-d₆) δ 8.07 (s, 1H), 7.85 (s, 1H), 6.68 (br s, 2H), 5.38 (d, J=3.7 Hz, 4H), 3.96-3.84 (m, 8H), 3.75-3.72 (m, 4H), 3.45-3.42 (m, 4H), 3.33-3.31 (m, 4H), 2.74-2.71 (m, 4H), 2.18-2.14 (m, 4H), 1.60-1.51 (m, 6H), 1.40 (s, 18H), 1.30-1.23 (m, 12H), 0.94-0.81 (m, 16H), −0.04 (s, 18H). LCMS (ES⁺) m/z 679 (M+H)⁺, RT 2.65 and 2.70 min.

Step 7: 1-[5-((2,3-Dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-amine (trifluoroacetate salt)

A solution of 1-bromo-2,3-dichlorobenzene (7.5 mg, 0.02 mmol), Pd₂(dba)₃ (1.0 mg, 0.001 mmol), Xantphos (1.3 mg, 0.002 mmol) and 2-ethylhexyl 3-[(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio]propanoate (Intermediate 4; 15 mg, 0.02 mmol) in toluene (0.6 mL) was degassed using a positive flow of N₂ for 5 min. Then ^(t)BuOK (49 μL, 0.05 mmol, 1.0 M in THF) was added dropwise and the reaction mixture was heated at 110° C. for 1 h. After cooling, the mixture was concentrated in vacuo, and diluted with DCM (1 mL) and NH₄Cl sat. sol. The resulting mixture was stirred vigorously for 10 min. The organic layer was separated and treated with TFA (68 μL, 0.88 mmol). The mixture was concentrated in vacuo and the residue was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column). Lyophilization of the appropriate fractions afforded the title compound as a white solid (2.9 mg, 25%). LCMS (ES⁺) m/z 409 (M+H)⁺; RT 1.2 min.

The following examples were synthesized using the procedure indicated in Scheme 1, by using in Step 7 the appropriate aryl halide instead of 1-bromo-2,3-dichlorobenzene, as indicated below:

Example ArX in step 7  1 3-bromo-2-(trifluoromethyl)pyridine  6 5-Bromo-1-methyl-1H-indazole  9 3-Bromothieno[2,3-c]pyridine  10 1-(4-bromophenyl)-4,5-dihydro-1H-1,2,4-triazol-5-one  11 Bromobenzene  12 3-bromopyridine  18 1-iodo-2-(trifluoromethyl)benzene  19 4-iodo-3-(trifluoromethyl)benzonitrile  20 1-iodo-2,4-difluorobenzene  21 1-bromo-2,3-difluorobenzene  23 2-bromobenzonitrile  24 1-iodo-2-methoxybenzene  25 1-iodo-3-methoxybenzene  26 3-iodobenzonitrile  27 1-bromo-4-(trifluoromethoxy)benzene  28 4-bromo-3-chloropyridine  29 1-(4-bromophenyl)-cyclobutanecarbonitrile  30 3-bromobenzo[b]thiophene  36 1-bromo-2-chloro-4-trifluoromethylbenzene  37 1,2-diiodoobenzene  38 1-iodo-4-chloro-2-methylbenzene  39 1-iodo-2,3-dimethylbenzene  45 1-iodo-4-methoxybenzene  46 1-bromo-3-cyclopropylbenzene  47 2-iodo-6-(trifluoromethyl)pyridine  48 4-(3-Bromophenyl)-2-methylthiazole  49 5-bromoquinoline  57 3-(5-Bromothiophen-2-yl)-1-methyl-5-(trifluoromethyl)-1H- pyrazole  58 3-bromo-1,1′-biphenyl  59 2-(4-Bromophenyl)-5-phenyl-1,3,4-oxadiazole  60 1-bromonaphthalene  61 4-bromoquinoline  62 4-bromo-1,5-naphthyridine  64 2,4-dibromopyridine  65 5-bromopyrazolo[1,5-a]pyrimidine  66 6-bromopyridin-2-ol  67 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine  68 2-bromo-3-methylthiophene  69 2-bromo-6-methoxyquinoline  70 5-bromoisoquinoline  71 5-bromoquinoxaline  73 3-bromo-2-chlorothiophene  74 (2-iodophenyl)pentafluoro-λ⁶-sulfane  75 1-(2-bromophenyl)-2-methylpropan-2-ol  76 7-bromo-2,3-dihydro-1H-inden-1-one  77 4-bromo-1,3-dihydroisobenzofuran  92 8-bromoisoquinoline  93 (6-bromophenyl)pentafluoro-λ⁶-sulfane  94 tert-butyl 3-bromobenzoate  95 tert-butyl 4-bromobenzoate  97 3-chloro-2-(trifluoromethyl)pyridine 100 5-bromoquinazoline 101 4-bromoquinazoline 102 2-(2-bromophenyl)thiazole 103 tert-butyl 2-(3-bromophenyl)acetate 104 7-bromopyrazolo[1,5-a]pyrimidine 105 4-bromo-1,8-naphthyridine 106 4-chloro-2-methylquinoline 116 2-[(4-iodobenzimidazol-1-yl)methoxy]ethyl-trimethyl-silane 130 tert-butyl (4-bromo-3-chloropyridin-2-yl)(methyl)carbamate 132⁽¹⁾ tert-butyl N-(4-bromo-3-chloro-pyridin-2-yl)-N- [(2-methylpropan-2-yl)oxycarbonyl]carbamate 134⁽¹⁾ 4-iodo-3,3-difluoro-1-methylindolin-2-one 135⁽¹⁾ 1-(4-iodo-3,3-difluoroindolin-1-yl)ethan-1-one 136⁽¹⁾ 4-iodo-2,2-difluorobenzo[d][1,3]dioxole 145⁽²⁾ tert-butyl N-(4-bromo-3-chloro-pyridin-2-yl)-N- [(2-methylpropan-2-yl)oxycarbonyl]carbamate 146⁽²⁾ tert-butyl (4-bromo-3-chloropyridin-2-yl)(methyl)carbamate 147⁽¹⁾ tert-butyl N-(4-bromo-3-chloro-pyridin-2-yl)-N-ethanoyl- carbamate 151⁽²⁾ 4-bromo-3-chloro-2-methoxypyridine 153⁽²⁾ 3-chloro-4-iodo-2-(oxetan-3-yloxy)pyridine (Intermediate 46) 154⁽²⁾ 3-chloro-4-iodo-N,N-dimethylpyridin-2-amine (Intermediate 47) 155⁽³⁾ 4-bromo-3-chloropyridine ⁽¹⁾2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide was used in Step 4 instead of tert-butyl N-(4-methylpiperidin-4-yl)carbamate ⁽²⁾Intermediate 7 was used in Step 4 instead of tert-butyl N-(4-methylpiperidin-4-yl)carbamate ⁽³⁾2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)propane-2-sulfmamide was used in Step 4 instead of tert-butyl N-(4-methylpiperidin-4-yl)carbamate

Examples 4 and 52: 4-methyl-1-(1-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine (Example 4) and 4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine (Example 52)

The compounds were prepared according to Scheme 2, following the procedures indicated below.

Step 1: 6-bromo-1-methyl-2-(methylthio)-1H-imidazo[4,5-b]pyrazine and 5-bromo-1-methyl-2-(methylthio)-1H-imidazo[4,5-b]pyrazine

A solution of 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-thione (Intermediate 1) (100 mg, 0.4 mmol, prepared as in Step 1, Scheme 1) in DMF (2.5 mL) under N₂ atmosphere was treated at 0° C. with NaH (43 mg, 1.1 mmol, 60% in mineral oil). The resulting yellow mixture was stirred at rt for 1 h. To this solution was added in one portion iodomethane (55 uL, 0.9 mmol) and mixture stirred for 1 h at rt. H₂O (2 mL) was added dropwise and mixture extracted with DCM (3×15 mL). Organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compound (1:1 mixture of regioisomers by ¹H NMR) as a yellow viscous oil (87 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.39 (s, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 2.80 (s, 6H). LCMS (ES⁺) m/z 259, 261 (M+H)⁺, RT 1.35 min.

Step 2: 6-bromo-1-methyl-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine and 5-bromo-1-methyl-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine

A solution of 6-bromo-1-methyl-2-(methylthio)-1H-imidazo[4,5-b]pyrazine and 5-bromo-1-methyl-2-(methylthio)-1H-imidazo[4,5-b]pyrazine (1:1 mixture of regioisomers; 87 mg, 0.3 mmol) in DCM (3 mL) was treated at 0° C. with m-CPBA (209 mg, 0.9 mmol). Mixture was stirred at rt for 3 h. NaHCO₃ sat. sol. (3 mL) was added dropwise and mixture was extracted with DCM (3×20 mL). Then organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compounds (1:1 mixture of regioisomers by ¹H NMR) as a white solid (90 mg, 98%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.88 (s, 1H), 4.10 (s, 3H), 4.07 (s, 3H), 3.66 (s, 6H). LCMS (ES⁺) m/z 291, 293 (M+H)⁺, RT 1.20 min.

Step 3: tert-butyl (1-(5-bromo-1-methyl-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate and tert-butyl (1-(6-bromo-1-methyl-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of 6-bromo-1-methyl-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine and 5-bromo-1-methyl-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine (1:1 mixture of regioisomers; 90 mg, 0.3 mmol) and tert-butyl N-(4-methylpiperidin-4-yl)carbamate (79.5 mg, 0.4 mmol) in 1,4-dioxane (2.5 mL) was heated at 110° C. for 4 h. Mixture was concentrated under reduced pressure. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compound as a mixture of regioisomers and as a white solid (40 mg, 30%). LCMS (ES⁺) m/z 425, 427 (M+H)⁺, RT 1.78 min.

Step 4: tert-butyl (4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate and tert-butyl (4-methyl-1-(1-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate

A vial was charged with DIPEA (33 uL, 0.2 mmol), tert-butyl (1-(5-bromo-1-methyl-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate and tert-butyl (1-(6-bromo-1-methyl-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (mixture of regioisomers) (40 mg, 0.09 mmol), potassium 2-(trifluoromethyl)pyridine-3-thiolate (82 mg, 0.19 mmol), Xantphos (5.4 mg, 0.01 mmol) and Pd₂(dba)₃ (4.3 mg, 0.005 mmol) in 1,4-dioxane (1 mL). The vial was sealed and heated at 120° C. for 1 h. Mixture was filtered through a pad of Solka Floc and concentrated under reduced pressure. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compound (2:1 mixture of regioisomers by UPLC) as a white solid (33 mg, 67%). LCMS (ES⁺) m/z 524 (M+H)⁺, RT 1.97, 2.02 min.

Step 5: Example 4 and Example 52: 4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine and 4-methyl-1-(1-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine

To a stirred solution of tert-butyl (4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate and tert-butyl (4-methyl-1-(1-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate (2:1 mixture of regioisomers) (33 mg, 0.06 mmol) in DCM (0.9 mL) at 0° C. was added TFA (97 uL, 1.3 mmol) and the reaction mixture was stirred at rt for 4 h. Volatiles were removed under reduced pressure and purification by reverse phase flash chromatography [gradient elution 0-100% MeCN (0.1% TFA) in H₂O (0.1% TFA)] gave the title compounds (2:1 mixture of regioisomers by ¹H NMR) as a white solid (22 mg, 82%).

Mixture was resolved by automated SFC using as stationary phase an IB™ CHIRALPAK©column and as mobile phase a linear gradient of MeOH in CO₂.

Example 4: 4-methyl-1-(1-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, J=4.5 Hz, 1H), 8.31 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.58-7.52 (m, 1H), 3.78-3.59 (m, 6H), 3.61 (s, 3H), 1.64-1.55 (m, 3H), 1.13 (s, 3H); ¹⁹F NMR (DMSO-d₆) δ −63.55. LCMS (ES⁺) m/z 424 (M+H)⁺, RT 1.14 min.

Example 52: 4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61-8.58 (m, 1H), 8.16 (s, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.61 (dd, J=8.2, 4.5 Hz, 1H), 3.69-3.67 (m, 3H), 3.73-3.56 (m, 4H), 1.65-1.44 (m, 4H), 1.12 (s, 3H); ¹⁹F NMR (DMSO-d₆) δ −63.26. LCMS (ES⁺) m/z 424 (M+H)⁺, RT 1.14 min.

Example 63: 1-(1-Ethyl-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to Scheme 3, following the procedures reported below.

Step 2: tert-butyl (6-bromo-3-chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate

A solution of 6-bromo-3-chloropyrazin-2-amine (500, 2.4 mmol) in DCM (5 mL) cooled to 0° C. was treated with (BoC)₂O (1.15, 5.28 mol), DMAP (29 g, 0.2 mmol) and TEA. The reaction mixture was stirred at 10 for 1 h then NaHCO₃ sat. sol. was added. The organic phase was separated and washed with HCl 1 N and brine. The dried organics were concentrated in vacuo to give the title compound as a pale yellow solid (92 mg, 94%) which was used in the next step without further purification. ¹H NMR (DMSO-d₆) δ 8.9 (s, 1H), 1.39 (s, 18H). LCMS (ES⁺) m/z 431 (M+Na)⁺; RT 2.48 min.

Step 2: tert-butyl (tert-butoxycarbonyl)(3-chloro-6-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)carbamate

A solution of tert-butyl (6-bromo-3-chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate (92 mg, 2.2 mmol) in 1,4-dioxane (1 mL) was treated with Pd₂(dba)₃ (12 mg, 0.1 mmol), Xantphos (163 mg, 0.28 mmol), [2-(trifluoromethyl)pyridin-3-yl]sulfanylpotassium (738 mg, 3.4 mmol) and DIPEA (0.97 mL, 5.6 mmol). The reaction mixture was heated at 100° C. for 30 min. After cooling, the mixture was filtered through a pad of Solka Floc and the organic solvent was concentrated in vacuo and the residue purified on silica gel (eluting with 0-60% EtOAc/Petroleum ether) to give the title compound as a yellow powder (970 mg, 840%). ¹H NMR (DMSO-d₆) δ 8.85 (dd, J=4.4 and 1.3 Hz, 1H), 8.64 (s, 1H), 8.3 (d, J=7.9 Hz, 1H), 7.84 (dd, J=8.1 and 4.6 Hz, 1H), 1.9 (s, 18H). LCMS (ES⁺) m/z 507 (M+H)⁺, RT 2.57 min.

Step 3: 3-Chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazin-2-amine

A solution of compound from Step 2 (970 mg, 1.91 mmol) in DCM (6 mL) was treated with TFA (2 L). The reaction mixture was stirred at rt for 4 h, cooled to 0° C. and diluted H₂O, NaHCO₃ sat. sol. was added until pH 8. The organic phase was separated, dried and concentrated in vacuo to give the title compound as a yellow solid (550 g, 94%) which was used in the next step without further purification. ¹H NMR (DMSO-d₆) δ 8.71 (dd, J=4.4 and 1.3 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.73 (dd, J=8.1 and 4.6 Hz, 1H), 7.49 (s, 1H), 7.1 (br s, 2H). LCMS (ES⁺) m/z 307 (M+H)⁺; RT 1.87 min.

Step 4: N²-Ethyl-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazine-2,3-diamine

A solution of 3-chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazin-2-amine (30 mg, 0.1 mmol), ethylamine (684 μL, 1.36 mmol, 2.0 M in THF) and DIPEA (51 μL, 0.29 mmol) in isoamyl alcohol (0.6 mL) was heated to 130° C. for 30 h. After cooling, the mixture was diluted with H₂O and EtOAc. The organic phase was separated, washed with brine, dried and concentrated in vacuo to give the title compound as an orange solid (30 mg, 97%) which was used in the next step without further purification. LCMS (ES⁺) m/z 316 (M+H)⁺; RT 1.68 min.

Step 5:1-Ethyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

N²-Ethyl-5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-pyrazine-2,3-diamine (31 mg, 0.10 mmol) and CDI (79 mg, 0.49 mmol) were dissolved in THE (1.2 mL) and the obtained mixture was stirred at 70° C. for 24 h. The solvent was concentrated in vacuo and the residue was purified on silica gel (eluting with 0-100% EtOAc/Petroleum ether) to give the title compound as an orange solid (15 mg, 46%). LCMS (ES⁺) m/z 342 (M+H)⁺; RT 1.79 min.

Step 6: 2-Chloro-1-ethyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine

A solution of 1-ethyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (15.5 mg, 0.045 mmol) in POCl₃ (0.42 mL, 4.54 mmol) was heated to 140° C. for 72 h. After cooling, the mixture was treated with NaHCO₃ sat. sol. and extracted with EtOAc. The organic extracts were washed with brine, dried and concentrated in vacuo to give the title compound as a yellow oil (11 mg) which was used in the next step without further purification. LCMS (ES⁺) m/z 360 (M+H)⁺; RT 1.85 min.

Step 7: 1-(1-Ethyl-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (trifluoroacetate salt)

A solution of 2-chloranyl-1-ethyl-5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-imidazo[4,5-b]pyrazine (11.3 mg, 0.03 mmol) and tert-butyl N-(4-methylpiperidin-4-yl)carbamate (8.2 mg, 0.04 mmol) in 1,4-dioxane (0.6 mL) was heated to 110° C. for 4 h. After cooling, the mixture was concentrated in vacuo and the residue diluted with DCM (0.5 mL) and treated with TFA (0.5 mL, 6.5 mmol). The mixture was stirred at 45° C. for 30 min, then concentrated in vacuo and the residue purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column). Lyophilization of the appropriate fractions afforded the title compound as an orange powder (8.1 mg, 56% over two steps). ¹H NMR (DMSO-d₆) δ 8.63 (d, J=4.4 Hz, 1H), 8.23 (1H, s), 7.99 (3H, br s), 7.84 (1H, d, J=7.9 Hz, 1H), 7.64 (dd, J=8.1 and 4.6 Hz, 1H), 4.21-4.16 (m, 2H), 3.85-3.81 (m, 2H), 3.49-3.44 (m, 2H), 1.93-1.80 (m, 4H), 1.40 (s, 3H), 1.40 (t, J=6.6 Hz, 3H). LCMS (ES⁺) m/z 438 (M+H)⁺; RT 1.21 min.

Example 13 was synthesized according to the above procedures (Scheme 3), by using cyclopropylmethylamine instead of ethyl amine in Step 4.

Example 129 was synthesized according to the above procedures (Scheme 3), by using 2-methoxyethylamine instead of ethyl amine in Step 4.

Example 72: 1-(1-Ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to Scheme 4, following the procedures reported below.

Step 1: tert-butyl (5-bromo-3-chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate

A solution of 5-bromo-3-chloropyrazin-2-amine (800 mg, 3.83 mmol) in DCM (8 mL) at 0° C. was treated with (Boc)₂O (1.84 g, 8.44 mmol) and DMAP (117 mg, 0.96 mmol). The mixture was stirred at rt for 1 h, then NaHCO₃ sat. sol. was added. The organic phase was separated and washed with 1N HCl, brine, dried and concentrated in vacuo to give the title compound as an orange solid (1.52 g, 97%). ¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 1.38 (s, 18H). LCMS (ES⁺) m/z 431 (M+Na)⁺; RT 2.54 min.

Step 2: tert-butyl (tert-butoxycarbonyl)(3-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)carbamate

A solution of tert-butyl (5-bromo-3-chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate (1.55 g, 3.72 mmol) in 1,4-dioxane (30 mL) at rt was treated with Pd₂(dba)₃ (213 mg, 0.23 mmol), Xantphos (269 mg, 0.46 mmol), [2-(trifluoromethyl)pyridin-3-yl]sulfanylpotassium (1.21 g, 5.57 mmol) and DIPEA (1.62 mL, 9.3 mmol). The reaction mixture was heated at 110° C. for 30 min. After cooling, the mixture was filtered through a pad of Solka Floc and the filtrates concentrated in vacuo. The residue was purified on silica gel (eluting with 0-60% EtOAc/Petroleum ether) to give the title compound as an orange solid (1.54 g, 82%). ¹H NMR (DMSO-d₆) δ 8.89 (dd, J=4.8, 1.3 Hz, 1H), 8.64 (s, 1H), 8.4 (d, J=7.4 Hz, 1H), 7.89 (dd, J=7.9 and 4.8 Hz, 1H), 1.9 (s, 18H). LCMS (ES⁺) m/z 507 (M+H)⁺; RT 2.61 min.

Step 3: 3-Chloro-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazin-2-amine

A solution of tert-butyl N-[3-chloro-5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-pyrazin-2-yl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.54 g, 3.03 mmol) in DCM (10 mL) was treated with TFA (10 mL, 130 mmol) and stirred at rt for 3 h. Then, the mixture was cooled to 0° C., diluted with H₂O and treated with NaHCO₃ sat. sol. until pH 8. The organic phase was separated, dried and concentrated in vacuo to give the title compound as a yellow solid (930 mg, 99%) which was used in the next step without further purification. LCMS (ES⁺) m/z 307 (M+H)⁺; RT 1.82 min.

Step 4: N²-Ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazine-2,3-diamine

A solution of 3-chloro-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazin-2-amine (30 mg, 0.1 mmol), ethylamine (1 mL, 2.02 mmol, 2.0 M in THF) and DIPEA (51 μL, 0.29 mmol) in isoamyl alcohol (0.60 mL) was heated at 140° C. for 24 h. After cooling, the mixture was diluted with H₂O and EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to give the title compound as an orange solid (30 mg, 97%) which was used in the next step without further purification. LCMS (ES⁺) m/z 316 (M+H)⁺; RT 1.48 min.

Step 5: 1-Ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

A solution of N²-ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazine-2,3-diamine (31 mg, 0.10 mmol) in THE (1.2 mL) at rt was treated with CDI (79 mg, 0.49 mmol). The reaction mixture was heated to 70° C. for 24 h. After cooling, the solvent was concentrated in vacuo and the residue purified on silica gel (eluting with 0-100% EtOAc/Petroleum ether) to give the title compound as an orange solid (15.5 mg, 46%). LCMS (ES⁺) m/z 342 (M+H)⁺; RT 1.76 min.

Step 6: 2-Chloro-1-ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazine

A solution of 1-ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (15 mg, 0.045 mmol) in POCl₃ (0.42 mL, 4.54 mmol) was heated to 110° C. for 48 h. After cooling, the mixture was diluted with NaHCO₃ sat. sol. and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to give the title compound as a yellow oil (16 mg, 24%) which was used in the next step without further purification. LCMS (ES⁺) m/z 360 (M+H)⁺; RT 1.79 min.

Step 7: 1-(1-Ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (trifluoroacetate salt)

A solution of 2-chloro-1-ethyl-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazine (16 mg, 0.044 mmol) and tert-butyl N-(4-methylpiperidin-4-yl)carbamate (11 mg, 0.05 mmol) in 1,4-dioxane (0.6 mL) was heated to 100° C. for 4 h. The mixture was concentrated in vacuo and the residue was diluted with DCM (0.5 mL) and treated with TFA (0.5 mL, 6.5 mmol). The mixture was stirred at 45° C. for 30 min. After cooling, the mixture was concentrated in vacuo and the residue was purified by RP chromatography (gradient elution 0-30% MeCN (+0.1% TFA)/H₂O (+0.1% TFA)) to give the title compound as an orange solid (3.2 mg, 16% over two steps). ¹H NMR (DMSO-d₆) δ 8.60 (d, J=4.4 Hz, 1H), 8.36 (s, 1H), 7.96 (br s, 3H), 7.77 (d, J=7.4 Hz, 1H), 7.59 (dd, J=7.9 and 4.4 Hz, 1H), 4.12-4.06 (m, 2H), 3.86-3.83 (m, 2H), 3.52-3.46 (m, 2H), 1.95-1.81 (m, 4H), 1.40 (s, 3H), 1.30 (t, J=7.5 Hz, 3H). LCMS (ES⁺) m/z 438 (M+H)⁺; RT 1.2 min.

Example 88: 4-methyl-1-(5-(quinolin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to Scheme 5, following the procedure indicated below.

A 4 mL vial was charged with tert-butyl (1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 3; 15 mg, 0.03 mmol, prepared as in Step 5, Scheme 1), 8-mercaptoquinoline hydrochloride (8.2 mg, 0.04 mmol) and Cs₂CO₃ (13.7 mg, 0.07 mmol) in DMSO (0.27 mL) and degassed with N₂ for 30 seconds. The reaction mixture was then irradiated with a blue LED Strip (λ455 nm) for 24 h at rt then was filtered on a SiO₂ cartridge (2 g) eluting with a DCM/EtOAc 1:1 (6 mL). The organic solvent was evaporated and DCM:TFA (1:1; 0.5 mL) were added. The mixture was stirred at 45° C. for 30 min then concentrated in vacuo to give a residue that was purified by preparative HPLC to give the title compound as a yellow powder (0.4 mg, 4%). LCMS (ES⁺) m/z 392 (M+H)⁺; RT 0.86 min.

The following examples were synthesized using the above procedure (Scheme 5), by reaction of Intermediate 3 with the appropriate aryl- or heteroaryl mercaptane instead of 8-mercaptoquinoline, as indicated below:

Example Ar-SH  78 methyl 2-mercaptobenzoate  80 pyridine-4-thiol  81 naphthalene-2-thiol  91 2-mercaptoquinazolin-4(3H)-one  98 2-chlorobenzenethiol  99 3-chloro-4-mercaptobenzoic acid 114 3-chloro-2-methylbenzenethiol 115 2-isopropyl-benzenethiol 117 2-(methylsulphonyl) benzenethiol

Example 107: (S)-1′-(5-[(2-(Trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 6, following the procedures reported below.

Step 1: 5-Bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

A solution of 5-bromo-2,3-pyrazindiamine (4.1 g, 21.7 mmol) and CDI (7.0 g, 43.4 mmol) in THE (120 mL) was heated to 60° C. for 72 h. Then, a second portion of CDI (7.0 g, 43.4 mmol) was added and heating to 60° C. was continued for 24 h. After cooling, the mixture was concentrated in vacuo and the residue was purified by RP chromatography (gradient elution 0-50% MeCN (+0.1% TFA)/H₂O (+0.1% TFA)). Evaporation of the fractions containing the desired product furnished a compound which was triturated with MeCN and filtered off to give the title compound as a beige solid (3.04 g, 65%). ¹H NMR (DMSO-d₆) δ 11.98 (br s, 1H), 11.91 (br s, 1H), 7.98 (s, 1H). LCMS (ES⁺) m/z 215, 217 (M+H)⁺; RT 0.76 min.

Step 2: 5-[(2-(Trifluoromethyl)pyridin-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Intermediate 5)

A solution of 5-bromanyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (1.0 g, 4.65 mmol) in 1,4-dioxane (47 mL) was degassed with N₂ for 5 min, then Pd₂(dba)₃ (0.21 g, 0.23 mmol), Xantphos (0.27 g, 0.47 mmol), 2-(trifluoromethyl)pyridine-3-thiol (1.19 g, 5.12 mmol) and DIPEA (1.62 mL, 9.3 mmol) were added sequentially. The reaction mixture was degassed with N₂ for further 5 min and heated to 100° C. for 2 h. After cooling, the mixture was concentrated in vacuo and the residue was treated with MeCN affording a precipitate which was filtered off to give the title compound as a beige solid (1.33 g, 91%). ¹H NMR (DMSO-d₆) δ 11.96 (br s, 2H), 8.56 (d, J=3.7 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.58 (dd, J=8.2 and 4.5 Hz, 1H). LCMS (ES⁺) m/z 314 (M+H)⁺; RT 1.24 min.

Step 3: 2-Chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazine

A solution of 5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (Intermediate 5; 1.3 g, 4.15 mmol) in POCl₃ (20 mL, 0.21 mol) was heated to 120° C. in a sealed vial for 8 h. After cooling, the mixture was concentrated in vacuo to give a residue that was purified by RP chromatography (gradient elution 0-100% MeCN (+0.1% TFA)/H₂O (+0.1% TFA)) to furnish the title compound as a pale yellow solid (0.26 g, 19%). ¹H NMR (DMSO-d₆) δ 8.71 (d, J=3.9 Hz, 1H), 8.55 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.70 (dd, J=8.1 and 4.6 Hz, 1H). LCMS (ES⁺) m/z 332 (M+H)⁺; RT 1.4 min.

Step 4: (S)-1′-(5-[(2-(Trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (trifluoroacetate salt)

A solution of 2-chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazine (50 mg, 0.15 mmol), 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide (prepared according to the procedure described in WO2018172984; 132 mg, 0.30 mmol) and DIPEA (0.11 mL, 0.60 mmol) in 1,4-dioxane (1.5 mL) was heated in a sealed vial to 100° C. for 4 h. After cooling, the mixture was concentrated in vacuo to give a residue that was dissolved with MeOH (8.5 mL) and treated with HCl (5 mL, 4.0 mmol, 1.25 M in MeOH). The mixture was stirred at rt for 24 h, then concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column). Lyophilization of the appropriate fractions afforded the title compound as a white powder (28 mg, 30%). ¹H NMR (DMSO-d₆) δ 8.57 (d, J=4.4 Hz, 1H), 8.24 (br s, 3H), 8.14 (br s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.59 (dd, J=8.2 and 4.5 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.40-7.30 (m, 3H), 4.42 (d, J=4.6 Hz, 1H), 4.17 (dd, J=33.1 and 14.0 Hz, 2H), 3.41 (t, J=12.2 Hz, 2H), 3.19 (d, J=16.4 Hz, 1H), 3.01 (d, J=16.2 Hz, 1H), 1.86-1.68 (m, 2H), 1.55 (t, J=12.3 Hz, 2H). LCMS (ES⁺) m/z 498 (M+H)⁺; RT 1.18 min.

Example 149 was prepared used the same procedure, by using 2-methyl-N-[(1R)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide (prepared according to the procedure described in WO2018172984) in Step 4.

The following examples were synthesized using the above procedure (Scheme 6), with the corresponding starting materials as indicated below:

Example Amine in Step 4  2 tert-butyl N-[(4R)-8-azaspiro[4.5]decan-4-yl]carbamate  3⁽¹⁾ tert-butyl N-[(4R)-8-azaspiro[4.5]decan-4-yl]carbamate  5 tert-butyl 1,7-diazaspiro[3.5]nonane-1-carboxylate  7 4-(Boc-amino)-piperidine  8 4-(Boc-aminomethyl) piperidine  14 tert-butyl pyrrolidin-3-ylcarbamate  15 tert-butyl azetidin-3-ylcarbamate  16 4-(Boc-aminomethyl)-piperidine  17 tert-Butyl 2,6-diazaspiro[3,5]nonane-6-carboxylate  31 piperidine  32 (1H-pyrazol-5-yl)methanamine  33 tert-butyl piperidin-3-ylcarbamate  34 tert-butyl 4-aminopiperidine-1-carboxylate  35⁽²⁾ 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3- yl)propane-2-sulfinamide  40 N-(piperidin-4-yl)methanesulfonamide  41 piperidin-4-ol  42 4-((1H-Imidazol-1-yl)methyl)piperidine  43 2-Imidazo[1,2-a]pyridin-2-yl-ethylamine  44 tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate  50 2H-indazol-5-amine  51 Piperidine-4-carboxamide  53 4-(1-methyl-1H-imidazol-4-yl)piperidine  54 tert-butyl (4-aminobutan-2-yl)carbamate  55 tert-butyl (azetidin-3-ylmethyl)carbamate  56 tert-butyl octahydro-2H-pyrazino[1,2-a]pyrazine-2-carboxylate  79 2-(1,4-diazepan-1-yl)ethan-1-ol  82 2-(4-(aminomethyl)piperidin-1-yl)ethan-1-ol  83 1-oxa-3,7-diazaspiro[4.5]decan-2-one  84 tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate  85 tert-butyl azepan-4-ylcarbamate  86 tert-butyl N-[1-(morpholin-2-yl)ethyl]carbamate  87 2-methyl-2-morpholinopropylamine  89 tert-butyl 2-(2-aminoethyl)piperidine-1-carboxylate  90 tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate  96 tert-butyl N-[(3S,4S)-3-methyl-2-oxa-8- azaspiro[4.5]decan-4-yl]carbamate 108 5,6,7,8-tetrahydro-1,6-naphthyridin-3-amine 109 tert-butyl 6-amino-8-oxabicyclo[3.2.1]octan-2-yl)carbamate 110 tert-butyl 4-(aminomethyl)piperidine-1-carboxylate 111 tert-butyl 3-(aminomethyl)morpholine-4-carboxylate 112 (2-morpholinopyridin-3-yl)methanamine 113 2,2-dimethyl-3-(pyridin-3-yl)propan-1-amine 123 3-morpholinopropylamine 124 tert-butyl 9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3- carboxylate 125 tert-butyl 3,9-diazabicyclo[4.2.l]nonane-9-carboxylate 126 tert-butyl 8-amino-5-azaspiro[3.5]nonane-5-carboxylate 127 tert-butyl ((8-azaspiro[4.5]decan-1-yl)methyl)carbamate 128 tert-butyl 4-(aminomethyl)-2-phenylpyrrolidine-1-carboxylate 139 N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 142 (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfonamide 143 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′- piperidin]-3-yl)propane-2-sulfinamide 150⁽³⁾ N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 258⁽⁴⁾ tert-butyl (4S)-4-((tert-butylsulfinyl)amino)-2-chloro-4,6- dihydrospiro[cyclopenta[d]thiazole- 5,4′-piperidine]-1′-carboxylate 259⁽⁵⁾ 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfmamide ⁽¹⁾2,3-dichloro-benzenethiol was used in step 2 instead of 2-(trifluoromethyl)pyridine-3-thiol ⁽²⁾2-amino-3-chloropyridine-4-thiol was used in step 2 instead of 2-(trifluoromethyl)pyridine-3-thiol ⁽³⁾3-chloropyridine-4-thiol was used in step 2 instead of 2-(trifluoromethyl)pyridine-3-thiol ⁽⁴⁾DMSO at 120° C. was used instead of 1,4-dioxane at 100° C. in step 4.1 and HCl in 1,4-dioxane was used instead of HCl in MeOH in step 4.2 ⁽⁵⁾The compound was synthesized by using Intermediate 40 as starting material and reacting the compound according to step 2, 3 and 4 of Scheme 6; 2,3-dichlorobenethiol was used in step 2 instead of 2-(trifluoromethyl)pyridine-3-thiol.

Example 118: (S)-1′-(6-Chloro-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 7, following the procedures reported below.

Example 118 Step 1: 5-Chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

A microwave vial was charged with POCl₃ (1.79 mL, 19.15 mmol), PCl₅ (425 mg, 2.04 mmol) and 5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (Intermediate 5; 400 mg, 1.28 mmol, prepared as in Step 2 of Scheme 6). The vial was sealed and heated to 130° C. for 2 h. After cooling, the mixture was diluted with MeCN and the precipitate was filtered off to give the title compound as a yellow solid (247 mg, 50%). ¹H NMR (DMSO-d₆) δ 12.15 (s, 1H), 11.96 (s, 1H), 8.67 (d, J=4.7 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.68 (dd, J=8.1 and 4.6 Hz, 1H). LCMS (ES⁺) m/z 348, 350 (M+H)⁺; RT 1.48 min.

Step 2: 2,5-Dichloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazine

A solution of 5-chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (83 mg, 0.22 mmol) in POCl₃ (1 mL, 10.74 mmol) was heated at 120° C. in a sealed vial for 14 h. After cooling, the mixture was concentrated in vacuo to give a residue that was purified by RP chromatography (gradient elution 0-100% MeCN (+0.1% TFA)/H₂O (+0.1% TFA)) to furnish the title compound as a pale yellow solid (21.3 mg, 27%). ¹H NMR (DMSO-d₆) δ 8.84 (d, J=4.4 Hz, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.84 (dd, J=7.9 and 4.6 Hz, 1H). LCMS (ES⁺) m/z 366, 368 (M+H)⁺; RT 1.69 min.

Step 3: (S)-1′-(6-Chloro-5-[(2-(trifluoromethyl)pyridin-3-yl)thio]-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (trifluoroacetate salt)

A solution of 2,5-dichloro-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine (10 mg, 0.03 mmol), 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide (17 mg, 0.05 mmol) and DIPEA (0.019 mL, 0.11 mmol) in 1,4-dioxane (0.3 mL) was heated in a sealed vial to 100° C. for 4 h. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in MeOH (1.6 mL) and treated with HCl (1 mL, 0.5 mmol, 1.25 M in MeOH) at rt for 20 h. The mixture was concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column). Lyophilization of the appropriate fractions afforded the title compound as a white powder (8.3 mg, 40%). ¹H NMR (DMSO-d₆) δ 8.71 (d, J=4.4 Hz, 1H), 8.23 (br s, 3H), 7.99 (d, J=7.9 Hz, 1H), 7.71 (dd, J=7.9 and 4.6 Hz, 1H), 7.49 (d, J=7.4 Hz, 1H), 7.40-7.28 (m, 3H), 4.45-4.37 (m, 1H), 4.17-4.05 (m, 2H), 4.08 (d, J=12.7 Hz, 1H), 3.39 (t, J=12.5 Hz, 2H), 3.18 (d, J=16.4 Hz, 1H), 3.00 (d, J=16.4 Hz, 1H), 1.84-1.67 (m, 2H), 1.54 (t, J=11.3 Hz, 2H). LCMS (ES⁺) m/z 532, 534 (M+H)⁺; RT 1.35 min.

Example 119: 4-Methyl-1-(5-[(2-(trifluoromethyl)pyridin-3-yl)thio]thiazolo[4,5-b]pyrazin-2-yl)piperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to Scheme 8, following the procedures reported below.

Step 1: 5-Bromothiazolo[4,5-b]pyrazine-2(3H)-thione

A solution of 6-bromo-3-chloropyrazin-2-amine (1.0 g, 4.80 mmol) and ethoxycarbothioylsulfanylpotassium (1.15 g, 7.20 mmol) in DMA (8.6 mL) was heated to 120° C. for 3 h. After cooling, the mixture was treated with AcOH (2 mL) and H₂O (50 mL) affording a precipitate which was filtered off to give the title compound as a yellow solid (0.64 g, 54%). ¹H NMR (DMSO-d₆) δ 8.58 (1H, s). LCMS (ES⁻) m/z 246, 248 (M−H)⁻; RT 1.40 min.

Step 2: 5-Bromo-2-(methylthio)thiazolo[4,5-b]pyrazine

A solution of 5-bromothiazolo[4,5-b]pyrazine-2(3H)-thione (320 mg, 1.29 mmol) in NaOH (79 mg, 1.93 mmol)/H₂O (9.1 mL) was treated with iodomethane (0.12 mL, 1.93 mmol). The reaction mixture was stirred at rt for 5 h, observing the formation of precipitate, which was filtered off and washed with H₂O and co-evaporated in vacuo with MeCN to give the title compound as a yellow solid (299 mg, 88%) which was used in the next step without further purification. ¹H NMR (DMSO-d₆) δ 8.73 (s, 1H), 2.86 (s, 3H). LCMS (ES⁺) m/z 262, 264 (M+H)⁺; RT 1.66 min.

Step 3: 5-Bromo-2-(methylsulfinyl)thiazolo[4,5-b]pyrazine

A solution of 5-bromo-2-(methylthio)thiazolo[4,5-b]pyrazine (290 mg, 1.11 mmol) in DCM (11 mL) at 0° C. was treated with mCPBA (600 mg, 2.43 mmol). The reaction mixture was stirred at rt for 2 h, then diluted with DCM and the organic phase was washed with NaHCO₃ sat. sol., brine, dried and concentrated in vacuo to give the title compound as a yellow solid (299 mg, 75%) which was used in the next step without further purification. ¹H NMR (DMSO-d₆) δ 9.17 (s, 1H), 3.67 (s, 3H). LCMS (ES⁺) m/z 278, 280 (M+H)⁺; RT 1.29 min.

Step 4: tert-Butyl [1-(5-bromothiazolo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate

A solution of 5-bromo-2-(methylsulfinyl)thiazolo[4,5-b]pyrazine (116 mg, 0.42 mmol) and tert-butyl N-(4-methylpiperidin-4-yl)carbamate (107 mg, 0.5 mmol) in 1,4-dioxane (2.3 mL) was heated to 100° C. for 20 h. After cooling, the mixture was concentrated in vacuo and the residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound as a yellow solid (170 mg, 95%). ¹H NMR (DMSO-d₆) δ 8.23 (s, 1H), 3.55-3.42 (m, 4H), 2.28-2.12 (m, 2H), 1.60-1.46 (m, 2H), 1.40 (s, 9H), 1.27 (s, 3H). LCMS (ES⁺) m/z 428, 430 (M+H)⁺; RT 2.06 min.

Step 5: 4-Methyl-1-(5-[(2-(trifluoromethyl)pyridin-3-yl)thio]thiazolo[4,5-b]pyrazin-2-yl)piperidin-4-amine (trifluoroacetate salt)

A microwave vial was charged with a solution of tert-butyl [1-(5-bromothiazolo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (30 mg, 0.06 mmol) in 1,4-dioxane (1 mL) and degassed with N₂ for 5 min. Then Pd₂(dba)₃ (2.8 mg, 0.003 mmol), Xantphos (3.6 mg, 0.006 mmol), [potassium 2-(trifluoromethyl)pyridine-3-thiolate (15 mg, 0.07 mmol) and DIPEA (20 μL, 0.12 mmol) were added sequentially. The reaction mixture was degassed with N₂ for further 5 min, then the vial was sealed and heated at 100° C. for 1 h. After cooling, the mixture was diluted with EtOAc and the organic phase was washed with H₂O, NaHCO₃ sat. sol. and brine. Aqueous phases were back extracted with EtOAc and the combined organic phases were dried and concentrated in vacuo to give a residue that was dissolved with DCM (0.9 mL) cooled to 0° C. and treated with TFA (0.1 mL, 1.3 mmol). The reaction mixture was stirred at rt for 3 h and concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C₁₈ column). Lyophilization of the appropriate fractions afforded the title compound as a white powder (23 mg, 69%). ¹H NMR (DMSO-d₆) δ 8.76 (d, J=3.7 Hz, 1H), 8.21 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.03 (br s, 3H), 7.76 (dd, J=8.1 and 4.6 Hz, 1H), 4.09-3.81 (m, 2H), 3.67-3.46 (m, 2H), 1.88-1.75 (m, 4H), 1.39 (s, 3H). LCMS (ES⁺) m/z 427 (M+H)⁺; RT 1.25 min.

Example 120: (R)-8-(5-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine

The compound was prepared according to Scheme 9, following the procedures reported below.

Step 1: (R)-8-(5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

A solution of 5-bromo-2-(methylthio)-1H-imidazo[4,5-b]pyrazine (300 mg, 1.08 mmol) (prepared as described in Example 22, Scheme 1, Step 3) and (4R)—N-[(1R)-1-(4-methoxyphenyl)ethyl]-8-azaspiro[4.5]decan-4-amine (prepared according to the procedure described in WO2017/216706; 374 mg, 1.3 mmol) in 1,4-dioxane (6.0 mL, 0.18 M) was heated at 120° C. for 4 h, then concentrated under reduced pressure and purified by flash chromatography [gradient elution 0-50% MeCN (+0.1% TFA) in H₂O (+0.1% TFA)]. The title compound was obtained as yellow solid (330 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (br s, 1H), 8.02 (br s, 1H), 7.93 (s, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.42-4.32 (m, 1H), 4.24 (br t, J=12.9 Hz, 2H), 3.77 (s, 3H), 3.26-3.08 (m, 3H), 2.08-1.89 (m, 2H), 1.77-1.66 (m, 2H), 1.64-1.47 (m, 8H), 1.38 (br d, J=12.7 Hz, 1H). LCMS (ES⁺) m/z 485 (M+H)⁺; RT 1.2 min;

Step 2: (R)-8-(5-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine

A microwave vial was charged with a solution of (R)-8-(5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (30 mg, 0.06 mmol) in toluene (1 mL, 0.06 M). The reaction mixture was degassed with N₂ for 5 min, then Pd(OAc)₂ (1.4 mg, 0.01 mmol) and tri-tert-butylphosphine (1.2 mg, 0.010 mmol) followed by 1,2,3,4-tetrahydro-1,5-naphthyridine (16.6 mg, 0.12 mmol) and sodium tert-butoxide (20.8 mg, 0.22 mmol) were added. The reaction mixture was degassed with N₂ for further 5 min and heated at 120° C. for 24 h. All reagents were added again, the reaction mixture was degassed with N₂ and heated for further 24 h. Then it was cooled to rt, diluted with EtOAc and filtered through a pad of Solka Floc (washing with MeOH). The filtrate was concentrated to dryness. The crude intermediate was dissolved with TFA and heated at 100° C. for 4 h. TFA was removed under reduced pressure and the crude product was purified by preparative HPLC to give the title compound as a yellow solid (4 mg, 10%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.86 (br s, 3H), 7.60 (dd, J=8.8, 5.5 Hz, 1H), 4.11-3.97 (m, 2H), 3.89-3.78 (m, 2H), 3.54-3.42 (m, 2H), 3.27-3.21 (m, 1H), 3.18 (br t, J=6.4 Hz, 2H), 2.17-2.05 (m, 3H), 1.87-1.74 (m, 3H), 1.74-1.61 (m, 4H), 1.60-1.46 (m, 2H). LCMS (ES⁺) m/z 405 (M+H)⁺; RT 0.4 min.

Example 121: tert-Butyl (1-[5-((2,3-dichlorophenyl)amino)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (trifluoroacetate salt)

The compound was prepared according to the Scheme 10, following the procedures below.

A solution of 2,3-dichloroaniline (7.0 mg, 0.04 mmol) in toluene (0.4 mL) at rt was treated with Pd₂(dba)₃ (1.3 mg, 0.001 mmol), BINAP (1.8 mg, 0.003 mmol), Cs₂CO₃ (19.5 mg, 0.06 mmol) and tert-butyl (1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 3; 16 mg, 0.03 mmol, prepared as in Step 5 of Scheme 1). The reaction mixture was degassed with N₂ for 5 min and heated to 110° C. for 18 h. After cooling, the mixture was concentrated in vacuo, diluted with DCM (1 mL) and NH₄Cl sat. sol. (0.5 mL) and stirred vigorously for 10 min. The organic phase was separated and treated with TFA (226 μL, 2.95 mmol) at rt for 2 h. The mixture was concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C₁₈ column). Lyophilization of the appropriate fractions afforded the title compound as a white solid (4.5 mg, 49%). ¹H NMR (DMSO-d₆) δ 8.42 (s, 1H), 7.94 (br s, 3H), 7.86-7.84 (m, 2H), 7.27-7.24 (m, 1H), 7.18-7.16 (m, 1H), 3.98-3.95 (m, 2H), 3.46-3.39 (m, 2H), 1.76-1.74 (m, 4H), 1.38 (s, 3H). LCMS (ES⁺) m/z 392 (M+H)⁺, 394 (M+Na)⁺, RT 1.01 min.

The same procedure indicated in Scheme 10 was used for the synthesis of Example 249, by reacting tert-butyl (S)-(1′-(5-bromo-1-((2-(tert-butyldimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate, prepared as indicated in steps 1 and 2 of Scheme 17, with 1,2,3,4-tetrahydro-1,5-napthyridine following the procedure indicated above.

Example 122: tert-Butyl [1-(5-(2,3-dichlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (trifluoroacetate salt)

The compound was prepared according to Scheme 11, following the procedure below.

A solution of 2,3-dichlorophenol (6.8 mg, 0.04 mmol) in 1,4-dioxane (0.4 mL) was treated with N,N-dimethylglycine (0.5 mg, 0.003 mmol), CuI (0.5 mg, 0.003 mmol), tert-butyl [1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-yl)carbamate (Intermediate 3; 5 mg, 0.03 mmol, prepared as in Step 5 of Scheme 1) and Cs₂CO₃ (18 mg, 0.06 mmol). The reaction mixture was heated at 110° C. for 24 h. After cooling, the mixture was concentrated in vacuo, diluted with DCM (1 mL) and NH₄Cl sat. sol. (0.5 mL) and stirred vigorously for 10 minutes. The organic phase was separated, treated with TFA (226 μL, 2.95 mmol) and stirred for 2 h at rt. Then, the mixture was concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column). Lyophilization of the appropriate fractions afforded the title compound as a yellow solid (6.5 mg, 60%). ¹H NMR (DMSO-d₆) δ 7.92 (br s, 3H), 7.83 (br s, 1H), 7.53 (dd, J=8.1 Hz, and J=1.3 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.22 (d, J=7.0 Hz, 1H), 3.98-3.96 (m, 2H), 3.44-3.41 (m, 2H), 1.79-1.75 (m, 4H), 1.38 (s, 3H). LCMS (ES⁺) m/z 393 (M+H)⁺, RT 1.22 min.

Example 131: 1-[5-(2,3-Dichlorophenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-methylpiperidin-4-amine (trifluoroacetate salt)

The compound was prepared according to Scheme 12, following the procedure below.

A microwave vial was charged with a solution of tert-butyl N-[1-(5-bromanyl-3H-imidazo[4,5-b]pyrazin-2-yl)-4-methyl-piperidin-4-yl]carbamate (Intermediate 2, prepared as in Step 4 of Scheme 1; 50 mg, 0.12 mmol), (2,3-dichlorophenyl)boronic acid (25 mg, 0.13 mmol) and Na₂CO₃ (39 mg, 0.36 mmol) in 1.2 mL 1,4-dioxane/H₂O (5:1) and degassed with N₂ for 5 min. Pd(PPh₃)₄ (42 mg, 0.04 mmol) was added and the reaction mixture was degassed with N₂ for further 5 min, then the vial was sealed and heated at 100° C. for 1 h. After cooling, the mixture was diluted with EtOAc and concentrated in vacuo to give a residue that was purified on silica gel (eluting with 10-100% EtOAc/Petroleum ether) to give the desired intermediate as a yellow solid (30 mg, 26%). This residue was dissolved with DCM (2 mL) at 0° C. and treated with TFA (0.2 mL, 2.64 mmol). The reaction mixture was stirred at rt for 20 h, then concentrated in vacuo to give a residue that was purified by preparative HPLC to give the title compound as a white powder (1.4 mg, 2%). ¹H NMR (DMSO-d₆) δ 12.57 (br s, 1H), 8.13 (br s, 1H), 7.94 (br s, 3H), 7.71 (dd, J=7.9 and 1.7 Hz, 1H), 7.56-7.44 (m, 2H), 4.12-3.97 (m, 2H), 3.63-3.45 (m, 2H), 1.84-1.74 (m, 4H), 1.40 (s, 3H). LCMS (ES⁺) m/z 375, 376, 377 (M+H)⁺; RT 1.08 min.

The procedure according to Scheme 12 was used for the synthesis of Example 140, by reacting (3-chloro-2-(methylamino)pyridin-4-yl)boronic acid instead of (2,3-dichlorophenyl)boronic acid with Intermediate 6; final deprotection was done with HCl in MeOH at room temperature).

Example 133: 1-(5-((2,3-dichlorophenyl)thio)-6-methyl-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine

The compound was prepared according to the Scheme 13, following the procedure below.

To a 4 mL glass vial equipped with a pressure release septa was added tert-butyl (1-(5-((2,3-dichlorophenyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (25 mg, 0.040 mmol) (prepared as described in Scheme 1, Example 22 Step 7, excluding the TFA treatment to avoid removal of the SEM and Boc protecting groups), Ir catalyst (0.9 mg, 0.001 mmol) in MeCN/TFA (1/1 v/v, 0.4 mL, 0.1 M) followed by tert-butyl ethaneperoxoate (0.07 mL, 0.120 mmol). The reaction mixture was degassed with N₂ for 15 min then irradiated with a 36 W Kessil blue LED lamp in presence of a fan for 6 h at rt. The reaction mixture was diluted with DMSO and filtered before purification by preparative HPLC. The title compound was obtained as yellow solid (0.6 mg, 3%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (br s, 3H), 7.60 (d, J=7.9 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 4.03-3.90 (m, 2H), 3.63-3.51 (m, 2H), 2.58 (s, 3H), 1.87-1.79 (m, 4H), 1.38 (s, 3H). LCMS (ES⁺) m/z 423 (M+H)⁺; RT 1.29 min.

Example 137: (S)-2-(2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-1-yl)acetamide (trifluoroacetate salt)

The compound was prepared according to Scheme 14, following the procedures below.

Step 1: (R)—N—((S)-1′-(5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate 6)

A solution of 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide; 2,2,2-tris(fluoranyl)ethanoic acid (650 mg, 1.08 mmol), DIPEA (0.79 mL, 4.51 mmol) and 6-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine (250 mg, 0.90 mmol, prepared as in Step 3 of Scheme 1) in 1,4-dioxane (9 mL) was heated at 120° C. for 48 h. The mixture was concentrated under reduced pressure and the crude material was purified on silica gel (eluting with 10-100% EtOAc/Petroleum ether) to give the desired intermediate as a yellow solid (190 mg, 41%). ¹H NMR (DMSO-d₆) δ 12.43 (br s, 1H), 7.95 (s, 1H), 7.29-7.19 (m, 4H), 5.69 (d, J=10.5 Hz, 1H), 4.45 (d, J=10.5 Hz, 1H), 4.19 (br s, 2H), 3.38-3.15 (m, 4H), 2.08 (td, J=12.8, 4.3 Hz, 1H), 1.80-1.59 (m, 2H), 1.38-1.33 (m, 1H), 1.20 (s, 9H). LCMS (ES⁺) m/z 503 (M+H)⁺; RT 1.62 min.

Step 2: 2-(5-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)acetamide

NaH (60% in mineral oil; 14 mg, 0.36 mmol) was put in a flask and DMF (1.8 mL, 0.023 mol) was added, then a solution of (R)—N—((S)-1′-(5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (90 mg, 0.180 mmol) in DMF (0.5 mL) was added dropwise at 0° C. The mixture was stirred for 15 min at rt. Then a solution of 2-iodoacetamide (66 mg, 0.360 mmol) in DMF (0.2 mL) was added dropwise at 0° C. After 1 h at rt the mixture was diluted with EtOAc and washed with H₂O. Organic phases were dried over Na₂SO₄, filtered and concentrated to dryness. The residue crude was purified on silica gel (eluting with 10-100% EtOAc+5% MeOH/Petroleum ether) to give the desired intermediate as a yellow powder (57 mg, 56%). ¹H NMR (DMSO-d₆) δ 7.79 (br d, J=7.0 Hz, 1H), 7.60 (s, 1H), 7.44 (br d, J=7.0 Hz, 1H), 7.26-7.21 (m, 4H), 5.65 (br dd, J=15.2, 10.4 Hz, 1H), 4.95-4.88 (m, 2H), 4.57-4.43 (m, 3H), 3.28-3.17 (m, 2H), 2.07-2.02 (m, 1H), 1.66 (br s, 2H), 1.34-1.36 (m, 2H), 1.27-1.12 (m, 10H). LCMS (ES⁺) m/z 561 (M+H)⁺; RT 1.29 min.

Step 3: (S)-2-(2-(J-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-1-yl)acetamide (trifluoroacetate salt)

A 4 mL vial was charged with 2-(5-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)acetamide (57 mg, 0.100 mmol), potassium 2-(trifluoromethyl)pyridine-3-thiolate (44 mg, 0.20 mmol), Cs₂CO₃ (66 mg, 0.20 mmol) in DMSO (0.8 mL) and degassed with N₂ for 30 seconds. The reaction mixture was then irradiated with a blue LED Strip (λ455 nm) for 24 h at rt then filtered on a SiO₂ cartridge (12 g) eluting with a mixture of DCM/EtOAc (1:9). The organic solvent was evaporated and the residue was dissolved in MeOH (0.5 mL) and a solution of HCl in MeOH (0.5 mL, 0.5 M) was added. The mixture was stirred at rt for 1 h then concentrated in vacuo to give a residue that was purified by prep HPLC to give the title compound as a yellow powder (0.6 mg, 3%). LCMS (ES⁺) m/z 555 (M+H)⁺; RT 0.95 min.

Example 138: 2-(2-(4-amino-4-methylpiperidin-1-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-1-yl)ethan-1-ol

The compound was prepared according to Scheme 15, following the procedures indicated below.

Step 1: tert-Butyl (4-methyl-1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate

A microwave vial was charged with a solution of tert-butyl (1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 3; 180 mg, 0.32 mmol, prepared as in Step 5 of Scheme 1), Pd₂(dba)₃ (10 mg, 0.02 mmol), Xantphos (20 mg, 0.03 mmol), potassium 2-(trifluoromethyl)pyridine-3-thiolate (80 mg, 0.36 mmol) and DIPEA (0.11 mL, 0.65 mmol) in 1,4-Dioxane (3.7 mL). The mixture was heated at 120° C. for 12 h. After cooling, the mixture was concentrated to dryness. The residue was purified on silica gel (eluting with 10-70% EtOAc/Petroleum Ether) to give the desired intermediate as a red solid (150 mg, 72%). ¹H NMR (DMSO-d₆) δ 8.73-8.72 (m, 0.5H), 8.62-8.61 (m, 0.5H), 8.56-8.55 (m, 0.5H), 8.34 (s, 0.5H), 8.12 (s, 0.5H), 7.86-7.83 (m, 1H), 7.83-7.70 (m, 1H), 7.64-7.61 (m, 1H), 7.55-7.52 (m, 1H), 6.70 (bs, 1H), 5.41 (s, 1H), 5.30 (s, 1H), 4.04-3.96 (m, 2H), 3.75 (t, J=7.89 Hz, 1H), 3.58 (t, J=7.89 Hz, 1H), 3.52-3.44 (m, 2H), 2.18-2.15 (m, 2H), 1.59-1.53 (m, 2H), 1.40 (s, 8.5), 1.26 (d, J=3.29 Hz, 3H) 1.11-1.07 (m, 1H), 0.96 (t, J=7.89 Hz, 1H), 0.84 (t, J=7.89 Hz, 1H), −0.04-0.04 (m, 4.5H), −0.10 (s, 4H). LCMS (ES⁺) m/z 640 (M+H)⁺; RT 2.62, 2.73 min (mixture of regioisomers).

Step 2: tert-butyl (4-methyl-1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate

tert-butyl (4-methyl-1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-yl)carbamate (150 mg, 0.230 mmol) was dissolved in THE (1.2 mL) and treated with TBAF (0.47 mL, 0.470 mmol) at reflux for 4 h. After cooling, the mixture was diluted in DCM and washed with H₂O. Organic phases were dried over Na₂SO₄, filtered and concentrated to dryness. The residue crude was purified on silica gel (eluting with 10-100% EtOAc/Petroleum ether) to give the desired intermediate as a yellow oil (57 mg, 48%). ¹H NMR (DMSO-d₆) δ 12.48 (br s, 1H), 8.55 (d, J=4.4 Hz, 1H), 8.10 (br s, 1H), 7.69 (br d, J=8.1 Hz, 1H), 7.58-7.55 (m, 1H), 6.67 (br s, 1H), 3.89-3.86 (m, 2H), 3.40-3.37 (m, 2H), 2.13 (br d, J=12.9 Hz, 2H), 1.51-1.47 (m, 2H), 1.39 (s, 9H), 1.25 (s, 3H). LCMS (ES⁺) m/z 510 (M+H)⁺; RT 1.75 min.

Step 3: tert-butyl (1-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

tert-butyl N-[4-methyl-1-[5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-1H-imidazo[4,5-b]pyrazin-2-yl]piperidin-4-yl]carbamate (57 mg, 0.110 mmol) was dissolved in DMF (1.1 mL) and NaH (60% in mineral oil; 5.4 mg, 0.130 mmol) was added at 0° C. The mixture was stirred for 15 min at rt and then 2-bromoethoxy-tert-butyl-dimethyl-silane (37 mg, 0.160 mmol), potassium iodide (18.57 mg, 0.110 mmol) were added. The reaction mixture was heated at 80° C. for 2 h. After cooling, the mixture was diluted in DCM and washed with H₂O. Organic phases were dried over Na₂SO₄, filtered and concentrated to dryness. The residue crude was purified on silica gel (eluting with 10-100% EtOAc/Petroleum Ether) to give the desired intermediate as a yellow solid (60 mg, 80%). LCMS (ES⁺) m/z 668 (M+H)⁺; RT 2.36 min.

Step 4: 2-(2-(4-amino-4-methylpiperidin-1-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-1-yl)ethan-1-ol (trifluoroacetate salt)

tert-butyl N-[1-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-imidazo[4,5-b]pyrazin-2-yl]-4-methyl-piperidin-4-yl]carbamate (60 mg, 0.090 mmol) was dissolved in DCM (0.5 mL) and treated with TFA (0.1 mL, 0.09 mmol) for 4 h at rt. The mixture was concentrated to dryness and the residue crude was purified by preparative HPLC to give the title compound as a yellow powder (11 mg, 27%). ¹H NMR (DMSO-d₆) δ 8.62 (d, J=4.6 Hz, 1H), 8.44 (s, 1H), 8.15 (br s, 3H), 7.90 (d, J=8.1 Hz, 1H), 7.63 (dd, J=8.1, 4.6 Hz, 1H), 4.47 (br t, J=5.0 Hz, 2H), 4.31 (br d, J=13.4 Hz, 1H), 4.00 (br d, J=13.2 Hz, 1H), 3.94-3.90 (m, 1H), 3.73 (br d, J=11.8 Hz, 2H), 1.93-1.81 (m, 4H), 1.76 (s, 1H), 1.41 (s, 3H). LCMS (ES⁺) m/z 454 (M+H)⁺; RT 0.82 min.

Example 144: 1-(2-((2,3-Dichlorophenyl)thio)-7H-purin-8-yl)-4-methylpiperidin-4-amine

The compound was prepared according to Scheme 16, following the procedures reported below.

Step 1: 2-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine

To a suspension of 2-chloro-7H-purine (1.0 g, 6.47 mmol) in THF was added NaH (388 mg, 9.7 mmol) in 60% mineral oil portion-wise (14 mL, 0.46 M) at 0° C. The reaction mixture was stirred at rt for 30 min, then cooled to 0° C. and treated with 2-(chloromethoxy)ethyltrimethylsilane (1.53 mL, 7.76 mmol). The reaction mixture was stirred at rt for 2 h. After careful addition of NH₄Cl sat. sol. the mixture was extracted with EtOAc. The dried organics were concentrated in vacuo to give the title compound (mixture of regioisomers) as a pale orange oil (1.93 g, 99%) which was used in the next step without further purification. LCMS (ES⁺) m/z 285 (M+H)⁺; RT 1.73, 1.88 min.

Step 2: 2-((2,3-Dichlorophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine

A solution of 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (200 mg, 0.70 mmol) in DMF (1 mL, 0.70 M) was treated with potassium carbonate (107 mg, 0.77 mmol) and 2,3-dichlorobenzenethiol (140 mg, 0.77 mmol). The reaction mixture was stirred at 80° C. for 12 h. After cooling, NH₄Cl sat. sol. was added and the mixture extracted with EtOAc. The dried organics were concentrated in vacuo. The residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound (mixture of regioisomers) as a yellow oil (145 mg, 48%). LCMS (ES⁺) m/z 427, 429 (M+H)⁺; RT 2.03, 2.15 min.

Step 3: 8-Chloro-2-((2,3-dichlorophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine

A solution of 2-((2,3-dichlorophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (30 mg, 0.07 mmol) in THE (1 mL, 0.07 M) was treated with (diisopropylamino)lithium (0.18 mL, 0.35 mmol) at −78° C. and stirred at this temperature for 1 h. 1,1,1,2,2,2-hexachloroethane (83 mg, 0.35 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h, then at rt for 30 min. After addition of NH₄Cl sat. sol. the mixture was diluted with EtOAc. The organic phase was separated and washed with brine, dried and concentrated in vacuo. The residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum ether) to give the title compound as a yellow foam (21 mg, 65%). LCMS (ES⁺) m/z 461 (M+H)⁺; RT 2.32 min.

Step 4: 1-(2-((2,3-Dichlorophenyl)thio)-7H-purin-8-yl)-4-methylpiperidin-4-amine (trifluoroacetate salt)

A solution of 8-chloro-2-((2,3-dichlorophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (21 mg, 0.05 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (12 mg, 0.05 mmol) and DIPEA (0.02 mL, 0.14 mmol) in 1,4-dioxane (0.5 mL, 0.1 M) was heated at 90° C. for 2 h. After cooling, the mixture was concentrated in vacuo and the residue diluted with DCM (0.5 mL, 0.08 M) and TFA (0.1 mL). The mixture was stirred at room temperature for 90 min, then concentrated in vacuo and the residue purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C₁₈ column). Lyophilization of the appropriate fractions afforded the title compound as a creamy powder (13 mg, 52% over two steps). ¹H NMR (DMSO-d₆) δ 8.28 (s, 1H), 7.95 (br s, 3H), 7.74 (d, J=8.0 Hz, 2H), 7.43 (t, J=8 Hz, 1H), 3.96-3.93 (m, 2H), 3.46-3.41 (m, 2H), 1.76-1.74 (m, 4H), 1.37 (s, 3H). LCMS (ES⁺) m/z 408 (M+H)⁺; RT 1.19 min.

Example 148: (S)-1′-(5-((2-chloropyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 17, following the procedures reported below.

Step 1: (S)-1′-(5-bromo-1-((2-(tert-butyldimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

A solution of (R)—N—((S)-1′-(5-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate 6; 640 mg, 1.27 mmol, prepared as in Step 1, Scheme 14) in DMF (12 mL) was treated with NaH (60% in mineral oil; 56 mg, 1.4 mmol) at 0° C. The mixture was stirred for 1 h at rt and 2-(chloromethoxy)ethyl-trimethylsilane (0.326 mL, 1.65 mmol) was added dropwise and then stirred for 12 h at rt. During this time, the sulfinimide protecting group of target molecule has been removed. The mixture was quenched with H₂O and diluted in DCM. Organic phases were dried over Na₂SO₄, filtered and evaporated under reduced pressure and the crude residue was purified on silica gel (eluting with 10-100% EtOAc/Petroleum ether) to give the desired intermediate as a yellow solid (240 mg, 35%). LCMS (ES⁺) m/z 529/531 (M+H)⁺; RT 1.79 min.

Step 2: tert-butyl (S)-(1′-(5-bromo-1-((2-(tert-butyldimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

A solution of (S)-1′-(5-bromo-1-((2-(tert-butyldimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (240 mg, 0.450 mmol) in DCM (2.3 mL) was treated with TEA (0.08 mL, 0.54 mmol) and tert-butoxycarbonyl tert-butyl carbonate (118 mg, 0.54 mmol) at rt for 1 h. Mixture was evaporated under reduced pressure and the residue crude was purified on silica gel (eluting with 10-50% EtOAc/Petroleum ether) to give the desired intermediate as a yellow powder (150 mg, 52%). ¹H NMR (DMSO-d₆) δ 8.24 (s, 0.25H), 8.04 (s, 0.65H), 7.24-7.18 (m, 5H), 5.40 (s, 1.4H), 5.37 (s, 0.6H), 4.83 (d, J=9.4 Hz, 0.8H), 4.09-4.06 (m, 1.5H), 3.75-3.70 (m, 2H), 3.56-3.52 (m, 2H), 3.26 (d, J=16.2 Hz, 1.2H), 2.79 (d, J=15.8 Hz, 1H), 1.76-1.65 (m, 3H), 1.39 (s, 10H), 0.95-0.88 (m, 2H), −0.04-−0.07 (m, 9H). LCMS (ES⁺) m/z 629/631 (M+H)⁺; RT 2.76, 2.74 min (mixture of regioisomers).

Step 3: (S)-1′-(5-((2-chloropyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (trifluoroacetate salt)

In a microwave vial was charged a solution of tert-butyl (S)-(1′-(5-bromo-1-((2-(tert-butyldimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate (21 mg, 0.030 mmol), potassium 3-chloropyridine-4-thiolate (13 mg, 0.04 mmol), DIPEA (0.01 mL, 0.07 mmol), Pd₂(dba)₃ (1.5 mg, 0.05 mmol) and Xantphos (1.9 mg, 0.1 mmol) in 1,4-dioxane (0.37 mL). The mixture was stirred at 120° C. for 12 h. The mixture was evaporated and the residue was dissolved in TFA (0.2 mL) and DCM (1 mL). After stirring at rt for 1 h, the mixture was concentrated under reduced pressure and the resultant residue was purified by prep HPLC to give the title compound as a white powder (4.6 mg, 29%). ¹H NMR (DMSO-d₆) δ 8.56 (s, 1H), 8.25 (br d, J=5.5 Hz, 5H), 7.51 (d, J=7.5 Hz, 1H), 7.41-7.31 (m, 4H), 6.80 (d, J=5.5 Hz, 1H), 4.44 (br d, J=5.0 Hz, 1H), 4.27-4.15 (br d, J=10.7 Hz, 3H), 3.21 (br d, J=16.2 Hz, 1H), 3.03 (br d, J=16.0 Hz, 1H), 1.87-1.71 (m, 2H), 1.67-1.52 (m, 2H). LCMS (ES⁺) m/z 464 (M+H)⁺; RT 1.03 min.

Example 141 was synthesized using the above procedure, by using potassium 3-sulfido-2-(trifluoromethyl)pyridine 1-oxide instead of potassium 3-chloropyridine-4-thiolate in Step 3.

Example 236 was prepared with the above procedure by using Intermediate 24 instead of potassium 3-chloropyridine-4-thiolate in Step 3.

Example 237 was prepared with the above procedure by using Intermediate 25 instead of potassium 3-chloropyridine-4-thiolate in Step 3.

Example 152: (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)pyridin-2(1H)-one

The compound was prepared according to Scheme 18, following the procedures indicated below.

Step 1: 2-ethylhexyl 3-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)propanoate

A pressure tube was charged with 5-bromo-2-methylsulfonyl-3H-imidazo[4,5-b]pyrazine (800 mg, 2.9 mmol) (prepared as described in Example 22, Scheme 1, Step 3), 2-ethylhexyl 3-mercaptopropanoate (722 uL, 3.2 mmol), DIPEA (1.0 mL, 5.8 mmol), Xantphos (83 mg, 0.14 mmol) and Pd₂(dba)₃ (66 mg, 0.07 mmol) in 1,4-dioxane (15 mL). The mixture was degassed with nitrogen for 1 min, capped and heated at 100° C. for 30 min. After cooling, the mixture was concentrated in vacuo and purified on silica gel (eluting with 10-100% EtOAc+10% MeOH/Petroleum ether) to give the title compound as a pale yellow solid (993 mg, 75%). LCMS (ES⁺) m/z 415 (M+H)⁺, RT 2.18 min.

Step 2: 3-chloro-4-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)pyridin-2(1H)-one

A solution of 2-ethylhexyl 3-[(2-methylsulfonyl-3H-imidazo[4,5-b]pyrazin-5-yl)sulfanyl]propanoate (35 mg, 0.08 mmol), 4-bromo-3-chloro-pyridin-2-ol (21 mg, 0.10 mmol), Xantphos (2.4 mg, 0.044 mmol), Pd₂(dba)₃ (1.93 mg, 0.002 mmol) were dissolved in 1,4-dioxane (0.5 mL) under nitrogen flux, then potassium 2-methylpropan-2-olate (126 uL, 0.126 mmol, 1 M in THF) and DIPEA (0.03 mL, 0.17 mmol) were added and stirred at 100° C. for 1 h. After cooling, the mixture was concentrated in vacuo and purified on silica gel (eluting with 10-100% EtOAc+20% MeOH/Petroleum Ether) to give the title compound as a yellow solid (8 mg, 26%). LCMS (ES⁺) m/z 358 (M+H)⁺, RT 0.84 min.

Step 3: (S)-4-((2-(I-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2(1H)-one

A solution of 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide; 2,2,2-tris(fluoranyl)ethanoic acid (12 mg, 0.03 mmol) and 3-chloro-4-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)pyridin-2(1H)-one (8 mg, 0.02 mmol) in 1,4-dioxane (0.2 mL) was treated with DIPEA (15 uL, 0.09 mmol) and stirred for 5 h at 120° C. The organic solvent was evaporated and the residue was dissolved in MeOH (0.3 mL) and a solution of HCl in MeOH (0.3 mL, 0.5 M) was added. The mixture was stirred at 4 for 2 h then concentrated in vacuo to give a residue that was purified by prep HPLC to give the title compound as a yellow powder (0.4 mg, 40%). 1H1 NMR (DMSO-d6) δ 11.97 (br d, J=5.5 Hz, 1H), 8.23 (br s, 4H), 7.50 (d, J=7.2 Hz, 1H), 7.40-7.31 (in, 3H), 7.21-7.18 (in, 1H), 5.53 (d, J=7.0 Hz, 1H), 4.42 (br d, J=4.2, 1H), 4.26-4.14 (m, 2H), 3.39 (t, J=12.5 Hz, 2H), 3.18 (d, J=16.4 Hz, 1H), 3.00 (d, J=16.4 Hz, 1H), 1.83-1.73 (m, 2H), 1.61-1.55 (in, 2H). LCMS (ES⁺) m/z 480 (M+H)⁺, RT 0.92 min.

The following compounds were prepared following the procedure indicated above, by using the in Step 2 and Step 3 the aromatic or heteroaromatic halide and the amine indicated in the table below

Example ArX in Step2 Amine in Step 3 155 4-bromo-3-chloropyridine 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3- yl)propane-2-sulfinamide 156 4-(trifluoromethyl)-5- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- bromopyrimidine piperidine]-1-yl]propane-2-sulfinamide 157 8-bromo-2H- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- benzo[b][1,4]oxazin-3(4H)-one piperidine]-1-yl]propane-2-sulfinamide 158 2-bromo-3-chloropyrazine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 159 2-amino-4-iodo-3- 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3- chloropyridine yl)propane-2-sulfinamide 160 4-iodo-3-chloro-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- (cyclopropylamino)pyridine piperidine]-1-yl]propane-2-sulfinamide 161 4-iodo-3-chloro-2- (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- (cyclopropylamino)pyridine piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 162 4-iodo-3,3-difluoroindolin-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- one piperidine]-1-yl]propane-2-sulfinamide 163 4-bromo-3-chloropyridine 2-methyl-N-((R)-3H-spiro[furo[3,2-b]pyridine-2,4′- piperidin]-3-yl)propane-2-sulfinamide (Intermediate 36) 164 4-bromo-1,5-naphthyridine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 166 4-bromo-3-chloro-1- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methylpyridin-2(1H)-one piperidine]-1-yl]propane-2-sulfinamide 167 5-bromo-2,3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- dihydrobenzo|b|[1,4]dioxine piperidine]-1-yl]propane-2-sulfinamide 168 6-iodo-4-chlorobenzo[d]oxazol- (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- 2(3H)-one piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 169 6-iodo-5-chloro-2H- (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- benzo[b][1,4]oxazin-3(4H)-one piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 170 5-bromo-3,4-dihydroquinolin- (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- 2(1H)-one piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 171 4-iodo-2,3-dichloropyridine (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 172 1-iodo-2,3-dichlorobenzene (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 174 3-chloro-N-cyclopropyl-4- 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3- iodopyridin-2-amine yl)propane-2-sulfinamide (Intermediate 31) 175 2-amino-3-chloro4-iodopyridine N-((S)-5-fluoro-1,3-dihydrospiro [indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 176 4-bromoquinoline 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 179 5-bromo-quinoxaline 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 180 4-(3-chloro-4-iodopyridin-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- yl)morpholine (Intermediate piperidine]-1-yl]propane-2-sulfinamide 41) 181 3-chloro-4-iodo-2-(3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methoxyazetidin-1-yl)pyridine piperidine]-1-yl]propane-2-sulfinamide (Intermediate 42) 183 4-bromo-3-chloropyridine N-((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 185 2-amino-4-bromo-5- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- chloropyridine piperidine]-1-yl]propane-2-sulfinamide 186 4-bromo-3-chloropyridine (R)-N-((S)-5-fluoro-6-methoxy-1,3-dihydrospiro[indene- 2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 33) 187 3-fluoro-4-iodopyridine N-((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 188 2-amino-3-chloro-4- N-((S)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′- iodopyridine piperidin]-1-yl)-2-methylpropane-2-sulfinamide 189 3-chloro-N-cyclopropyl-4- N-((S)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′- iodopyridin-2-amine piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate 31) 190 2-amino-4-bromo-3- N-((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- methoxypyridine 1-yl)-2-methylpropane-2-sulfinamide 191 1-(3-chloro-4-iodopyridin-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- yl)azetidine-3-carbonitrile piperidine]-1-yl]propane-2-sulfinamide (Intermediate 39) 192 8-bromoimidazo[1,2-a]pyridine N-((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 193 6-iodoindole 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 194 8-bromopyrido[2,3-b]pyrazine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 195 4-iodo-3-chloro-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methylpyridine piperidine]-1-yl]propane-2-sulfinamide 198 4-bromoindole 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 199 2-amino-4-iodo-3- N-((S)-5-fluoro-1,3-dihydrospiro [indene-2,4′-piperidin]- chloropyridine 1-yl)-2-methylpropane-2-sulfinamide 200 4-bromo-3-ethoxypyridine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- (Intermediate 14) piperidine]-1-yl]propane-2-sulfinamide 201 4-iodo-2- 2-methyl-N-((R)-3H-spiro[benzofuran-2,4′-piperidin]-3- (methylamino)nicotinonitrile yl)propane-2-sulfinamide (Intermediate 15) 202 7-iodo-2-methyl-2H-indazole 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 203 2-amino-4-iodo-3- N-((S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- chloropyridine 1-yl)-2-methylpropane-2-sulfinamide 204 4-iodo-3-chloro-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methylpyridine piperidine]-1-yl]propane-2-sulfinamide 205 2-amino-4-iodo-3- N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4′- chloropyridine piperidin]-3-yl)-2-methylpropane-2-sulfinamide 206 2-amino-3-chloro-4- N-((S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- iodopyridine 1-yl)-2-methylpropane-2-sulfinamide 207 3-chloro-4-iodopyridine N-((S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-yl)-2-methylpropane-2-sulfinamide 209 3-chloro-4-iodo-2-methylamino- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- pyridine piperidine]-1-yl]propane-2-sulfinamide 210 3-amino-4-iodopyridine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 211 3-bromo-N,N-dimethylpyridin- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- 2-amine(Intermediate 16) piperidine]-1-yl]propane-2-sulfinamide 212 7-bromothieno[3,2-b]pyridine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 213 4- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- bromobenzo[c][1,2,5]oxadiazole piperidine]-1-yl]propane-2-sulfinamide 214 3-iodo-2-methoxypyridine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 215 2-amino-4-iodonicotinonitrile 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- (Intermediate 17) piperidine]-1-yl]propane-2-sulfinamide 216 2-(benzyloxy)-5- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- bromoquinoxaline piperidine]-1-yl]propane-2-sulfinamide (Intermediate 18) 217 3-bromopicolinonitrile 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 218 4-bromo-5-fluoroquinoline 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 219 2-amino-3-chloro-4- N-((S)-5-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]- iodopyridine 3-yl)-2-methylpropane-2-sulfinamide 220 4-bromo-6-methoxy-1,5- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- naphthyridine piperidine]-1-yl]propane-2-sulfinamide 221 3-bromo-4H-pyrido[1,2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- a]pyrimidin-4-one piperidine]-1-yl]propane-2-sulfinamide (Intermediate 19) 222 2-amino-3-fluoro-4- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- iodopyridine piperidine]-1-yl]propane-2-sulfinamide 223 2-amino-3-chloro-4- 2-methyl-N-((S)-5-morpholino-1,3-dihydrospiro[indene- iodopyridine 2,4′-piperidin]-3-yl)propane-2-sulfinamide(Intermediate 48) 224 3-iodo-N-methylpicolinamide 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- (Intermediate 20) piperidine]-1-yl]propane-2-sulfinamide 225 3-bromo-2-(pyrrolidin-1- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- yl)pyridine (Intermediate 21) piperidine]-1-yl]propane-2-sulfinamide 226 4-bromo-3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- trifluoromethoxypyridine piperidine]-1-yl]propane-2-sulfinamide 227 4-(((4-iodoopyridin-3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- yl)oxy)methyl)-2-methyloxazole piperidine]-1-yl]propane-2-sulfinamide (Intermediate 45) 228 4-Bromo-3-chloro-2- N-((S)-5-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]- methoxypyridine 3-yl)-2-methylpropane-2-sulfinamide 229 2-amino-3-chloro-4- Intermediate 43 iodopyridine 230 2-amino-3-chloro-4- Intermediate 43 iodopyridine 231 3-iodo-2-methoxypyridine N-((S)-5-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]- 3-yl)-2-methylpropane-2-sulfinamide 232 4-bromo-1H-pyrrolo[2,3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- b]pyridine piperidine]-1-yl]propane-2-sulfinamide 233 2-amino-3-chloro-4- 2-methyl-N-(2-methylspiro[4,6- iodopyridine dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-4- yl)propane-2-sulfinamide (Intermediate 44) 239 4-Bromo-3-chloro-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methoxypyridine piperidine]-1-yl]propane-2-sulfinamide 240 4-bromo-1H-pyrrolo[2,3- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- b]pyridine-3-carbonitrile piperidine]-1-yl]propane-2-sulfinamide 241 4-bromo-5-chloropyridin-2-ol 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- (Intermediate 26) piperidine]-1-yl]propane-2-sulfinamide 242 4-bromo-5-chloro-2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- methoxypyridine piperidine]-1-yl]propane-2-sulfinamide 244 2-amino-3-chloro-4- (R)-N-((S)-5-(hydroxymethyl)-1,3-dihydrospiro[indene- iodopyridine 2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 34) 245 2-amino-3-chloro-4- (R)-N-((S)-5-(fluoromethyl)-1,3-dihydrospiro[indene- iodopyridine 2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 37) 246 3-chloro-N-ethyl-4-iodopyridin- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- 2-amine (Intermediate 27) piperidine]-1-yl]propane-2-sulfinamide 247 3,4-bis(chloro)pyridazine 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- piperidine]-1-yl]propane-2-sulfinamide 251 8-bromo-6-chloroimidazo[1,2- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- b]pyridazine piperidine]-1-yl]propane-2-sulfinamide 252 2-amino-3-chloro-4- (R)-N-((S)-5-(hydroxymethyl)-1,3-dihydrospiro[indene- iodopyridine 2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate 38) 254 4-bromo-8-methyl-1,5- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- naphtyridine piperidine]-1-yl]propane-2-sulfinamide 255 4-chloro-2-methyl-2H- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- pyrazolo[3,4-b]pyridine piperidine]-1-yl]propane-2-sulfinamide 256 2-amino-3-chloro-4- N-((S)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]- iodopyridine 3-yl)-2-methylpropane-2-sulfinamide 257 2-amino-3-chloro-4- (R)-N-((S)-5-cyclopropyl-1,3-dihydrospiro[indene-2,4′- iodopyridine piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 35) 260 2-amino-4-bromo-3- N-((R)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]- chloropyridine 3-yl)-2-methylpropane-2-sulfmamide⁽¹⁾ 261 7-bromo-1-methyl-1H- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- pyrazolo[4,3-b]pyridine piperidine]-1-yl]propane-2-sulfmamide (Intermediate 29) 262 4-bromo-2-chloro-3- (S)-N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- trifluoromethylpyridine piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7) 266 tert-butyl N-[5,6-bis(chloro)-4- 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′- iodo-pyridin-2-yl]carbamate piperidine]-1-yl]propane-2-sulfmamide ⁽¹⁾N-((R)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide was obtained as minor diastereoisomer (25%) sodium borohydride reduction of tert-butyl (R,Z)-1-((tert-butylsulfinyl)imino)-6-cyano-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (prepared as described in WO 2018/172984).

Example 165: (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidin-3-ol

The compound was prepared according to Scheme 19, following the procedures indicated below.

Step 1: 2-ethylhexyl 3-((3-chloro-2-fluoropyridin-4-yl)thio)propanoate

3-chloro-2-fluoro-4-iodopyridine (500 mg, 1.9 mmol), 2-ethylhexyl 3-mercaptopropanoate (424 mg, 1.9 mmol), Pd₂(dba)₃ (89 mg, 0.1 mmol), Xantphos (112 mg, 0.2 mmol) and DIPEA (0.68 mL, 3.9 mmol) were dissolved in 1,4-dioxane (13 mL) and the obtained mixture was degassed using a positive flow of N₂ and heated at 100° C. for 30 min. After cooling, the solvent was concentrated in vacuo and the residue was purified on silica gel (eluting with 0-30% Petroleum Ether/EtOAc) to give the title compound as a yellow oil (617 mg, 91%). LCMS (ES⁺) m/z 348 (M+H)⁺, RT 2.66.

Step 2: 2-ethylhexyl 3-((3-chloro-2-(3-hydroxyazetidin-1-yl)pyridin-4-yl)thio)propanoate

2-ethylhexyl 3-((3-chloro-2-fluoropyridin-4-yl)thio)propanoate (50 mg, 0.14 mmol), 3-hydroxyazetidin-1-ium 2,2,2-trifluoroacetate (86.6 mg, 0.29 mmol) and DIPEA (0.1 mL, 0.57 mmol) were dissolved in DMA (1 mL) and the obtained mixture was stirred at 60° C. for 18 h. The solvent was concentrated and EtOAc was added and washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound was obtained as a yellow oil (57 mg, 99%). LCMS (ES⁺) m/z 401 (M+H)⁺, RT 2.1 min.

Step 3: 2-ethylhexyl 3-((3-chloro-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)azetidin-1-yl)pyridin-4-yl)thio)propanoate

2-ethylhexyl 3-((3-chloro-2-(3-hydroxyazetidin-1-yl)pyridin-4-yl)thio)propanoate (126 mg, 0.3 mmol), was dissolved in DCM (2.0 mL) then pyridinium p-toluenesulfonate (PPTS, 39.4 mg, 0.16 mmol) and 3,4-dihydro-2H-pyran (DHP, 132 mg, 1.6 mmol) were sequentially added. The mixture was stirred at 20° C. for 18 h then the solvent was concentrated. Purification by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether) gave the title compound as a yellow oil (127 mg, 83%). LCMS (ES⁺) m/z 485 (M+H)⁺, RT 2.8 min.

Step 4: 5-((3-chloro-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)azetidin-1-yl)pyridin-4-yl)thio)-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine

The reaction was made following the procedure reported in Scheme 18, Step 2. The reaction was performed using 1 eq of ^(t)BuOK (126 μL, 0.13 mmol, 1.0 M in THF).

Step 5: (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidin-3-ol

The reaction was made following the procedure reported in the Scheme 18, Step 3 to obtain the title compound (7.8 mg, 14%). ¹H NMR (DMSO-d₆) δ 8.3 (br s, 3H), 8.26 (s, 1H), 7.73 (d, J=6.58 Hz, 1H), 7.52 (d, J=6.58 Hz, 1H), 7.39-7.30 (m, 3H), 6.15 (d, J=6.14 Hz, 1H), 4.54-4.51 (m, 3H), 4.47-4.42 (m, 1H), 4.26-4.14 (m, 2H), 4.06-4.05 (m, 2H), 3.49 (t, 2H), 3.22 (d, J=16.6 Hz, 1H), 3.03 (d, J=15.8 Hz, 1H), 1.86-1.78 (m, 2H), 1.63-1.59 (m, 2H). LCMS (ES⁺) m/z 535 (M+H)⁺; RT 1.22 min.

Example 238 was synthesized using the above procedure by reacting 3-iodo-1H-pyridin-2-one as indicated in Step 1 to obtain 2-ethylhexyl 3-((2-oxo-1,2-dihydropyridin-3-yl)thio)propanoate and then further reacting said compound as indicated in Step 4 and in Step 4.1

The following examples were synthesized using the procedures of Steps 4 and 5 in Scheme 19 above, with the corresponding starting materials: 173 (synthesized by using Intermediate 11 as starting material), 177 (synthesized by using Intermediate 12 as starting material), 178 (synthesized by using Intermediate 13 as starting material), 182 (synthesized by using Intermediate 12 as starting material and N—((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide in Step 5), 184 (synthesized by using Intermediate 32 as starting material and N—((S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide in Step 5), 234 (synthesized by using Intermediate 22 as starting material), 235 (synthesized by using Intermediate 23 as starting material), 269 (synthesized by using Intermediate 30 as starting material)

Examples 196 and 197: (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine and (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine

The compounds were prepared according to Scheme 20, following the procedures indicated below.

Step 1: spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-one 2,2,2-trifluoroacetate

A solution of tert-butyl 5-oxidanylidenespiro[7H-cyclopenta[c]pyridine-6,4′-piperidine]-1′-carboxylate (prepared as reported in WO 2020094018; 500 mg, 1.65 mmol) in DCM (13 mL) cooled to 0° C. was treated with TFA (1.3 mL). The reaction mixture was stirred at rt for 4 h. Volatiles were removed under reduced pressure to get a residue which was dissolved in MeCN/H₂O and lyophilized to remove excess of TFA. The title compound was obtained as an orange sticky solid (750 mg) and was used as such. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.78-8.76 (m, 1H), 8.73 (br d, J=4.0 Hz, 1H), 8.51 (br s, 1H), 7.65 (br d, J=4.0 Hz, 1H), 3.39-3.36 (m, 2H), 3.13-3.04 (m, 2H), 2.07 (s, 2H), 1.94-1.88 (m, 2H), 1.68-1.65 (m, 2H). LCMS (ES⁺) m/z 203 (M+H)⁺, RT 0.32 min.

Step 2: 1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-one

A solution of 3-chloro-N-cyclopropyl-4-[(2-methylsulfonyl-1H-imidazo[4,5-b]pyrazin-5-yl)sulfanyl]pyridin-2-amine (200 mg, 0.500 mmol; prepared following the procedure described in Scheme 18, Step 1 and Step 2, by using 4-iodo-3-chloro-2-cyclopropylamine in Step 2 instead of 4-bromo-3-chloropyridin-2-ol), spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-one 2,2,2-trifluoroacetate (227 mg, 0.760 mmol) and DIPEA (0.27 mL, 1.51 mmol) in 1,4-dioxane (5.0 mL) was heated at 120° C. for 18 h. 1,4-dioxane was removed in vacuo and the residue was purified by RP chromatography (0-50% MeCN (+0.1% TFA) in H₂O (+0.1% TFA)) to get the title compound as a brown residue (290 mg, 70% pure, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.72 (d, J=8.0 Hz, 1H), 8.19 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.14 (br s, 1H), 6.06 (d, J=4.0 Hz, 1H), 4.32 (br d, J=12.0 Hz, 2H), 3.46 (br t, J=12.0 Hz, 2H), 3.32 (s, 2H), 2.72 (br m, 1H), 1.80 (br t, J=8.0 Hz, 2H), 1.64 (br d, J=12.0 Hz, 2H), 0.74 (br d, J=4.0 Hz, 2H), 0.60 (br s, 2H). LCMS (ES⁺) m/z 519-521 (M+H)⁺, RT 1.02 min.

Step 3: (R)—N-(1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-ylidene)-2-methylpropane-2-sulfinamide

A solution of 1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-one from Step 2 (85 mg, 0.160 mmol) in THE (2.5 mL) was treated with TiOEt₄ (0.34 mL, 1.64 mmol) and 2-methylpropane-2-sulfinamide (79.4 mg, 0.660 mmol) and the mixture stirred at 90° C. for 72 h. After cooling down the mixture was concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-20% MeOH in EtOAc). The title compound was obtained as a white solid (71 mg, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (bs, 1H), 8.90 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 8.18-8.14 (br m, 2H), 7.76 (d, J=4.0 Hz, 1H), 6.59 (s, 1H), 5.94 (d, J=4.0 Hz, 1H), 4.35 (br d, J=12.0 Hz, 2H), 3.40 (br t, J=12.0 Hz, 2H), 2.74 (m, 1H), 1.99-1.80 (m, 2H), 1.75-1.70 (m, 2H), 1.22 (s, 9H), 0.66 (d, J=4.0 Hz, 2H), 0.54 (br s, 2H). LCMS (ES⁺) m/z 623 (M+H)⁺, RT 1.17 min.

Step 4: (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine and (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine (196 and 197)

A solution of (R)—N-(1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)spiro[cyclopenta[c]pyridine-6,4′-piperidin]-5(7H)-ylidene)-2-methylpropane-2-sulfinamide (50 mg, 0.08 mmol) in THF (1.0 mL) was cooled at −50° C. Sodium borohydride (9.1 mg, 0.240 mmol) was added portionwise and the resulting mixture was left stirring at rt for 16 h. The reaction mixture was quenched with few drops of H₂O, diluted with MeCN, concentrated under reduced pressure and purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column) to afford the title compounds as a white powder (11.6 mg of (R,S)-diasteroisomer, 23%; 11.8 mg of (R,R)-diasterisomer, 24%). LCMS (ES⁺) m/z 625 (M+H)⁺, RT 0.88 min; 0.94 min.

(R,S)-diastereoisomer mixture (11.6 mg, 0.019 mmol) was dissolved in MeOH (1.5 mL) and a solution of HCl in MeOH (0.08 mL, 1.25 M) was added. The mixture was stirred at rt for 18 h then was concentrated in vacuo to give a residue that was purified by RP-HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C₁₈ column). Lyophilization of the appropriate fractions afforded the title (S) compound as a white powder (6.48 mg, 66%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.45 (br s, 3H), 8.18 (br s, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.56 (d, J=4.0 Hz, 1H), 5.97 (d, J=4.0 Hz, 1H), 4.57 (br s, 1H), 4.23-4.19 (m, 2H), 3.45-3.40 (m, 2H), 3.32 (d, J=16.0 Hz, 1H), 3.05 (d, J=16.0 Hz, 1H), 2.78-2.69 (m, 1H), 1.93-1.90 (m, 1H), 1.70-1.66 (m, 2H), 1.48-145 (m, 1H), 0.72-0.70 (m, 2H), 0.57-0.55 (m, 2H). LCMS (ES⁺) m/z 521 (M+H)⁺, RT 0.65 min.

(R,S)-diasteroisomers mixture was treated as described above affording the title (R) compound as a white powder (7.54 mg, 76%). ¹H NMR (DMSO-d₆) δ 8.64 (s, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.45 (br s, 3H), 8.19 (br s, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.57 (d, J=4.0 Hz, 1H), 5.97 (d, J=4.0 Hz, 1H), 4.57 (br s, 1H), 4.24-4.19 (m, 2H), 3.45-3.40 (m, 2H), 3.32 (d, J=16.0 Hz, 1H), 3.05 (d, J=16.0 Hz, 1H), 2.78-2.69 (m, 1H), 1.93-1.90 (m, 1H), 1.70-1.66 (m, 2H), 1.48-145 (m, 1H), 0.72-0.70 (m, 2H), 0.57-0.55 (m, 2H). LCMS (ES⁺) m/z 521 (M+H)⁺, RT 0.63 min.

Example 208: (S)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-ol

A solution of (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (Example 205; 27 mg, 0.050 mmol) in DCM (1.0 mL) was treated with tribromoborane (27 uL, 0.03 mmol) the resulting mixture reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo to give a residue that was purified by preparative using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column) to afford the title compound as a white powder (3.5 mg, 13%). ¹H NMR (DMSO-d₆) δ 9.50 (s, 1H), 8.25-8.15 (m, 4H), 7.65 (d, J=5.7 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 6.77 (dd, J=8.1 and 2.2 Hz, 1H), 6.44-6.69 (m, 2H), 5.92 (d, J=5.7 Hz, 1H), 4.37-4.33 (m, 1H), 4.29-4.10 (m, 2H), 3.65-3.55 (m, 2H), 3.07 (d, J=16.0 Hz, 1H), 2.88 (d, J=16.0 Hz, 1H), 1.87-1.68 (m, 2H), 1.64-1.51 (m, 2H). LCMS (ES⁺) m/z 495 (M+H)⁺; RT 0.77 min.

Example 243: (S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 21, following the procedures indicated below.

Step 1: 2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine

2-Bromo-4H-pyrrolo[2,3-b]pyrazine (820 mg, 4.14 mmol), 2,3-dichlorobenzenethiol (816 mg, 4.56 mmol), Pd₂(dba)₃ (379 mg, 0.410 mmol) and Xantphos (240 mg, 0.410 mmol) were dissolved in a mixture of 1,4-dioxane (17 mL)/DMF (10 mL) and DIPEA (0.74 mL, 12.42 mmol) was added. The mixture was bubbled with N₂ and then heated at 120° C. for 30 min. The mixture was concentrated in vacuo and the residue treated with EtOAc. The solid obtained was filtered and dried to give the title compound as a brown solid (900 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.38 (s, 1H), 7.99 (br t, J=4.0 Hz, 1H), 7.56 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.06 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H), 6.65 (br d, J=4.0 Hz, 1H). LCMS (ES⁺) m/z 296-298 (M+H)⁺, RT 1.91 min.

Step 2: 2-((2,3-dichlorophenyl)thio)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine

2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine (900 mg, 3.04 mmol) was dissolved in THE (6.0 mL) then the mixture was cooled to 0° C. and sodium hydride (60% wt; 170 mg, 4.25 mmol) was added. After 30 min benzenesulfonyl chloride (0.39 mL, 3.04 mmol) was added and the mixture was stirred at rt for 1 h. The reaction mixture was cooled to 0° C. and NH₄Cl saturated solution was added followed by DCM. The organic phase was isolated, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether). The title compound was obtained as a white solid (882 mg, 67%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.13 (br d, J=8.0 Hz, 2H), 7.78 (br t, J=8.0 Hz, 1H), 7.67 (br t, J=8.0 Hz, 3H), 7.46 (dd, J₁=4.0 Hz, J₂=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.99 (d, J=4.0 Hz, 1H). LCMS (ES⁺) m/z 437 (M+H)⁺; RT 2.41 min.

Step 3: 6-chloro-2-((2,3-dichlorophenyl)thio)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine

2-((2,3-dichlorophenyl)thio)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.230 mmol) dissolved in THE (1.1 mL, 0.014 mol) and cooled to −78° C. was treated with (diisopropylamino)lithium (0.13 mL, 0.250 mmol). The mixture was stirred at −78° C. for 30 min then benzenesulfonyl chloride (0.04 mL, 0.280 mmol) was added and the solution stirred at this temperature for 5 min. NaHCO₃ saturated solution and EtOAc were added then the organic phase was isolated and washed with Na₂S₂O₃, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether). The title compound was obtained as a yellow solid (80 mg, 74%). LCMS (ES⁺) m/z 471 (M+H)⁺; RT 2.51 min.

Step 4: (S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

6-chloro-2-((2,3-dichlorophenyl)thio)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (8 mg, 0.020 mmol), 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide (8.3 mg, 0.020 mmol) and DIPEA (0.01 mL, 0.070 mmol) were dissolved in 1-Butanol (0.14 mL) and the mixture was heated at 160° C. for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC. The title compound was obtained as a yellow solid (2.5 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.23 (br s, 3H), 7.94 (s, 1H), 7.52-7.47 (m, 2H), 7.40-7.31 (m, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.88 (dd, J₁=4.0 Hz, J₂=8.0 Hz, 1H), 4.44-4.41 (m, 1H), 3.93-3.81 (m, 2H), 3.33-3.25 (m, 2H), 3.10 (dd, J₁=16.0 Hz, J₂=60.0 Hz, 2H), 1.86-1.78 (m, 2H), 1.55 (br d, J=16.0 Hz, 2H). LCMS (ES⁺) m/z 496 (M+H)⁺; RT 1.39 min.

Example 248: (S)-1′-(7-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 22, following the procedures indicated below.

Step 1: (R)—N—((S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

The reaction was performed following the procedure reported in the scheme 21 step 4 but under microwave irradiation, starting from 6-chloro-2-((2,3-dichlorophenyl)thio)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine prepared as described in the synthesis of Example 243, steps 1/2/3, Scheme 21.

Step 2: (R)—N—((S)-1′-(7-bromo-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

(R)—N—((S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20 mg, 0.030 mmol) was dissolved in DCM (0.35 mL) then a solution of 1-bromopyrrolidine-2,5-dione (6 mg, 0.030 mmol) in DCM (0.35 mL) was slowly added at 0° C. The mixture was stirred 5 min at 0° C. and 5 min at rt and then quenched with saturated aqueous NaHCO₃ and extracted with DCM. The organic layer was separated, dried over Na₂SO₄ and concentrated in vacuo to get the title compound as a yellow solid (22 mg, 63%) which was used as crude in the next step. LCMS (ES⁺) m/z 679-681 (M+H)⁺; RT 2.46 min.

Step 3: (S)-1′-(7-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

(R)—N—((S)-1′-(7-bromo-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20 mg, 0.029 mmol) was dissolved in HCl in MeOH (0.5 mL) and the mixture was stirred at rt for 30 min. The mixture was concentrated in vacuo and purified by preparative HPLC. The title compound was obtained as a yellow solid (3.6 mg, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 8.25 (br s, 3H), 8.06 (s, 1H), 7.51 (br d, J=8.0 Hz, 2H), 7.40-7.31 (m, 3H), 7.25 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 4.46-4.42 (m, 1H), 4.14 (dd, J₁=12.0 Hz, J₂=40.0 Hz, 2H), 3.44 (t, J=12.0 Hz, 2H), 3.11 (dd, J₁=16.0 Hz, J₂=64.0 Hz, 2H), 1.94-1.84 (m, 2H), 1.59 (br d, J=12.0 Hz, 2H). LCMS (ES⁺) m/z 532 (M+H)⁺; RT 1.80 min.

Example 250: (1S)-1′-[5-[5-(aminomethyl)-2-methoxy-pyridin-3-yl]sulfanyl-1H-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4′-piperidine]-1-amine

The compound was prepared using the procedure described in Scheme 18, wherein 2-((5-bromo-6-methoxypyridin-3-yl)methyl)isoindoline-1,3-dione (Intermediate 28) was used in Step 2 instead of 4-bromo-3-chloro-pyridin-2-ol. The procedure led to N-[(1S)-1′-[5-[5-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]-2-methoxy-pyridin-3-yl]sulfanyl-1H-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]-2-methyl-propane-2-sulfinamide which was further deprotected as described below.

A solution of N-[(1S)-1′-[5-[5-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]-2-methoxy-pyridin-3-yl]sulfanyl-1H-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]-2-methyl-propane-2-sulfinamide (prepared as described in Scheme 1; 21 mg, 0.030 mmol) in MeOH (0.500 mL) was treated with hydrazine hydrate (9 uL, 0.120 mmol). The resulting mixture was heated at 70° C. for 1 h. The mixture was concentrated under reduced pressure and treated with HCl (1.25 M in MeOH, 1 mL) and stirred for 2 h at rt. The mixture was concentrated in vacuo to give a residue that was purified by preparative HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column) to afford the title compound as a white powder (4.5 mg, 32%). ¹H NMR (DMSO-d₆) δ 8.29 (bs, 3H), 8.11 (s, 1H), 8.03 (bs, 4H), 7.54-7.51 (m, 2H), 7.34-7.30 (m, 3H), 4.44-4.41 (m, 1H), 4.22-4.18 (m, 2H), 3.94-3.86 (m, 6H), 3.20 (d, J=16.0 Hz, 1H), 3.02 (d, J=16.0 Hz, 1H), 1.81-1.75 (m, 2H), 1.58-1.54 (m, 2H). LCMS (ES⁺) m/z 489 (M+H)⁺; RT 0.72 min.

Example 253: methyl (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate

The compound was prepared according to Scheme 23, following the procedures indicated below.

Step 1: methyl 2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate

Methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (600 mg, 2.34 mmol), 2,3-dichlorobenzenethiol (462 mg, 2.58 mmol), Pd₂(dba)₃ (215 mg, 0.230 mmol) and Xantphos (136 mg, 0.230 mmol) were dissolved in 1,4-dioxane (5.0 mL)/DMF (2.8 mL) then DIPEA (0.74 mL, 7.03 mmol) was added and the mixture was heated at 120° C. for 30 min. The solvent was concentrated in vacuo and DCM and Et₂O were added to the residue. The obtained brown solid was filtered, dried and used in the next step as a crude. LCMS (ES⁺) m/z 353 (M+H)⁺; RT 1.83 min.

Step 2: methyl 6-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate

Methyl 2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (115 mg, 0.162 mmol) was dissolved in DCM (1.4 mL, 0.115 M) then 1-chloropyrrolidine-2,5-dione (65 mg, 0.486 mmol) was added and the mixture was stirred in a pre-heated bath at 75° C. for 20 h. NaHCO₃ saturated solution was added and the organic phase was isolated, dried over Na₂SO₄, filtered and concentrated in vacuo to afford a residue which was purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether). The title compound was obtained as a yellow solid (13 mg, 21%). ¹H NMR (DMSO-d₆) δ 8.38 (s, 1H), 7.63 (d, J=7.95 Hz, 1H), 7.36-7.30 (m, 1H), 7.30 (br s, 1H), 3.77 (s, 3H). LCMS (ES⁺) m/z 388-390 (M+H)⁺; RT 1.93 min.

Step 3: methyl (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate

Methyl 6-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (12 mg, 0.030 mmol), 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide (13 mg, 0.030 mmol) and DIPEA (0.02 mL, 0.120 mmol) were dissolved in 1-Butanol (0.26 mL) and the obtained mixture was stirred 15 min at 140° C. under microwave irradiation. The solvent was concentrated in vacuo and HCl in MeOH (0.3 mL) was added. The mixture was stirred at rt for 15 min then concentrated in vacuo and the residue was purified by C18 cartridge (gradient elution 0-30% MeCN+0.01% TFA in H₂O+0.1% TFA). The title compound was obtained as a yellow solid (8.6 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.27 (br s, 3H), 8.06 (s, 1H), 7.53 (t, J=8.0 Hz, 2H), 7.40-7.31 (m, 3H), 7.27 (t, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 4.48-4.43 (m, 1H), 3.93 (dd, J₁=12.0 Hz, J₂=40.0 Hz, 2H), 3.68 (s, 3H), 3.44 (t, J=12.0 Hz, 2H), 3.10 (dd, J₁=16.0 Hz, J₂=56.0 Hz, 2H), 1.97-1.88 (m, 2H), 1.63-1.55 (m, 2H). LCMS (ES⁺) m/z 554-556 (M+H)⁺; RT 1.49 min.

Example 263: (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine

The compound was prepared according to Scheme 24, following the procedures indicated below.

Step 1: (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine

To a solution of (S)-2-chloro-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine (Example 258 prepared as reported in Scheme 6) (5.14 mg, 0.010 mmol) in MeOH (1 mL), triethylsilane (0.03 mL, 0.190 mmol) and TEA (1% mol) were sequentially added. The resulting mixture was stirred at rt for 12 h. After removal of the solvent the crude was purified by preparative HPLC affording the title compound (2 mg, 39%). LCMS (ES⁺) m/z 505 (M+H)⁺, RT 2.16 min.

Example 264: (5S)-1′-[5-[2-(methylamino)-3-(trifluoromethyl)pyridin-4-yl]sulfanyl-1H-imidazo[4,5-b]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidine]-5-amine

A solution of (R)—N—((S)-1′-(5-((2-chloro-3-(trifluoromethyl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide (obtained according to the procedure described in Scheme 18 for the synthesis of Example 262, without the deprotection step 3.2); 25 mg, 0.040 mmol) and methanamine (2 mL, solution 2M in THF) in DMSO (0.5 mL, 0.007 mol) was heated at 100° C. in a sealed vial for 12 h. Additional methanamine (2 mL, solution 2M in THF) was added and the mixture was stirred for 5 h at 100° C. The mixture was concentrated in vacuo, HCl (0.5 mL, solution 1.2 M in MeOH) was added and stirred at 40° C. for 30 min. The solution was evaporated and the residue was purified by preparative HPLC using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (Cis column), to give the title compound as a yellow powder (0.4 mg, 2%). LCMS (ES⁺) m/z 528 (M+H)⁺; RT 0.82 min.

Example 265: (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The compound was prepared according to Scheme 25, following the procedures indicated below.

Step 1: 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

2-Bromo-4H-pyrrolo[2,3-b]pyrazine (1 g, 5.05 mmol) was dissolved in DMF (34 mL), and the resulting solution was cooled to 0° C. and sodium hydride (60% wt; 242 mg, 6.06 mmol) was added. The mixture was stirred at this temperature for 30 min then 2-(chloromethoxy)ethyl-trimethylsilane (0.99 mL, 5.55 mmol) was added and the mixture stirred for further 5 min. NaHCO₃ saturated solution and EtOAc were added to the mixture. The organic phase was then isolated, washed with H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue which was purified by flash chromatography (gradient elution 0-60% EtOAc in Petroleum Ether). The title compound was obtained as a pale yellow oil (1410 mg, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.14 (d, J=4.0 Hz, 1H), 6.73 (d, J=4.0 Hz, 1H), 5.63 (s, 2H), 3.51 (t, J=8.0 Hz, 2H), 0.81 (t, J=8.0 Hz, 2H), 0.11 (s, 9H). LCMS (ES⁺) m/z 328-330 (M+H)⁺, RT 2.36 min.

Step 2: 2-ethylhexyl 3-((5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)thio)propanoate

2-ethylhexyl 3-sulfanylpropanoate (1032 mg, 4.72 mmol), DIPEA (1665 mg, 12.89 mmol), Pd₂(dba)₃ (393 mg, 0.430 mmol) and Xantphos (249 mg, 0.430 mmol) were dissolved in 1,4-dioxane (11 mL) and 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1410 mg, 4.3 mmol) was added. The mixture was stirred at 110° C. for 1 h then the solvent was concentrated in vacuo and the residue purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether). The title compound was obtained as a yellow oil (2000 mg, 66% pure, 66%). LCMS (ES⁺) m/z 466 (M+H)⁺; RT 2.55 min.

Step 3: 3-chloro-4-((5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)thio)pyridin-2-amine

The reaction was performed following the procedure reported in Scheme 25, Step 2 and the title compound was obtained as a yellow oil after purification by flash chromatography (gradient elution 0-80% EtOAc in Petroleum Ether) (240 mg, 14%). ¹H NMR (DMSO-d₆) δ 8.56 (s, 1H), 8.21 (d, J=4.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 6.82 (d, J=4.0 Hz, 1H), 6.39 (br s, 2H), 5.83 (d, J=8.0 Hz, 1H), 5.67 (s, 2H), 3.55 (t, J=8.0 Hz, 2H), 0.83 (t, J=8.0 Hz, 2H), 0.10 (s, 9H). LCMS (ES⁺) m/z 408 (M+H)⁺; RT 1.62 min.

Step 4: 3-chloro-4-((6-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)thio)pyridin-2-amine

The reaction was performed following the procedure reported in Scheme 21, Step 3 and the title compound was obtained as a yellow solid after purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) (25 mg, 33%). LCMS (ES⁺) m/z 442 (M+H)⁺; RT 2.14 min.

Step 5: (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

The reaction was performed following the procedure reported for the preparation of Example 253 in Scheme 23, Step 3. The title compound was obtained as a yellow solid (1.9 mg, 7%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.95 (s, 1H), 8.24 (br s, 3H), 8.00 (s, 1H), 7.63 (d, J=4.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.40-7.31 (m, 3H), 6.72 (br s, 1H), 5.87 (d, J=8.0 Hz, 1H), 5.73 (s, 1H), 4.46-4.39 (m, 1H), 3.89 (br dd, J₁=12.0 Hz, J₂=28.0 Hz, 2H), 3.32-3.26 (m, 2H), 3.09 (dd, J₁=12.0 Hz, J₂=60.0 Hz, 2H), 1.89-1.77 (m, 2H), 1.55 (br d, J=12.0 Hz, 2H). LCMS (ES⁺) m/z 478 (M+H)⁺; RT 0.86 min.

The following examples were synthesized using the above procedure (Scheme 25) with the corresponding starting materials: Example 267 (wherein Intermediate 7 was used in Step 5 instead of 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide) and Example 268 (wherein 2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide was used in Step 5 instead of 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4′-piperidine]-1-yl]propane-2-sulfinamide).

Intermediate 7: (S)—N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfonamide

The compound was prepared according to Scheme 26, following the procedures reported below.

Step 1: tert-butyl (S)-5-((1,1-dimethylethyl)sulfonamido)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (50 mg, 0.120 mmol; prepared as described in WO2018/172984) in acetic acid (0.3 mL, 0.4 M) cooled to 0° C. was treated with hydrogen peroxide (30 wt. % in H₂O, 0.010 mL, 0.130 mmol), then heated at 60° C. for 4 h. The reaction mixture was concentrated to dryness and purified by flash chromatography (gradient elution 0-20% MeOH in DCM). The title compound was obtained as white solid (53 mg, 100%). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=5.0 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.22-7.14 (m, 1H), 4.60 (br d, J=11.0 Hz, 1H), 4.16 (br d, J=10.0 Hz, 1H), 4.11-3.85 (m, 2H), 3.17 (d, J=16.9 Hz, 1H), 2.97-2.75 (m, 3H), 1.82 (td, J=12.9, 4.6 Hz, 1H), 1.59 (td, J=11.4, 4.4 Hz, 1H), 1.53-1.46 (m, 1H), 1.43 (s, 9H), 1.40 (s, 9H), 1.33-1.23 (m, 1H). LCMS (ES⁺) m/z 424 (M+H)⁺, RT 1.44 min.

Step 2: (S)—N-(5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfonamide (Intermediate 7)

A stirred solution of tert-butyl (S)-5-((1,1-dimethylethyl)sulfonamido)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (53 mg, 0.13 mmol) in DCM (1 mL, 0.12 M) cooled to 0° C. was treated with TFA (0.1 mL, 1.31 mmol). The reaction mixture was stirred at rt for 4 h, then concentrated under reduced pressure. The title product was obtained as white solid (55 mg, 100%) and used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (br s, 1H), 8.37 (d, J=4.8 Hz, 1H), 8.24 (br s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.41 (d, J=9.6 Hz, 1H), 7.31-7.22 (m, 1H), 4.56 (br d, J=9.6 Hz, 1H), 3.35-3.27 (m, 1H), 3.25-3.15 (m, 2H), 3.09 (d, J=16.7 Hz, 1H), 3.05-2.90 (m, 1H), 2.86 (d, J=16.7 Hz, 1H), 2.02-1.87 (m, 1H), 1.82-1.70 (m, 1H), 1.66-1.55 (m, 1H), 1.32 (s, 9H), 1.22-1.13 (m, 1H). LCMS (ES⁺) m/z 324 (M+H)⁺, RT 0.59 min.

Intermediate 7 was used for the synthesis of Example 139, 142, 145, 146, 150, 151, 153, 154, 161, 168, 169, 170, 171, 172, 173, 174, 262, 264 and 267.

Intermediate 8: 4-chloro-6-iodobenzo[d]oxazol-2(3H)-one

Step 1: 4-chlorobenzo[d]oxazol-2(3H)-one

2-amino-3-chlorophenol (500 mg, 3.5 mmol) was dissolved in THE (20 mL) then CDI (903 mg, 5.6 mmol) was added. The mixture was stirred at 65° C. for 2 h then the reaction was cooled and concentrated. The residue was dissolved in EtOAc and washed with H₂O, 2M HCl, brine and dried over Na₂SO₄. The title compound was obtained as yellow solid (590 mg, 99%). LCMS (ES⁺) m/z 170 (M+H)⁺, RT 1.2 min.

Step 2: 4-chloro-6-iodobenzo[d]oxazol-2(3H)-one

I₂ (150 mg, 0.59 mmol) and Ag₂SO₄ (184 mg, 0.59 mmol) were dissolved in EtOH (6 mL) then 4-chlorobenzo[d]oxazol-2(3H)-one (100 mg, 0.59 mmol) was added and the obtained mixture was stirred for 18 h at 20° C. The resulting suspension was filtered through a pad of solka floc and the solvent was concentrated. EtOAc and NaHCO₃ sat. sol. were added and the organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compounds as a white solid (120 mg, 48%). LCMS (ES⁺) m/z 295 (M+H)⁺, RT 1.6 min.

The Intermediate 8 was used to synthesize compound 168.

Intermediate 9: 5-chloro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one

Step 1: 5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one

2-amino-3-chlorophenol (200 mg, 1.4 mmol), 2-chloroacetyl chloride (189 mg, 1.7 mmol) and K₂CO₃ (577 mg, 4.2 mmol) were dissolved in DMF (35 mL) and the mixture was stirred at 50° C. for 15 h. The resulting suspension was filtered through a pad of solka floc and the solvent was concentrated. EtOAc and NaHCO₃ sat. sol. were added and the organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (240 mg, 94%). LCMS (ES⁺) m/z 184 (M+H)⁺, RT 1.2 min.

Step 2: 5-chloro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one

I₂ (498 mg, 2.0 mmol) and Ag₂SO₄ (611 mg, 2 mmol) were dissolved in EtOH (13 mL) then 5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (240 mg, 1.3 mmol) was added and the obtained mixture was stirred for 18 h at 20° C. The resulting suspension was filtered through a pad of solka floc and the solvent was concentrated. EtOAc and NaHCO₃ sat. sol. were added and the organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-40% EtOAc in Petroleum Ether) gave the title compounds as a white solid (77 mg, 20%, 75% pure). LCMS (ES⁺) m/z 310 (M+H)⁺, RT 1.26 min.

The intermediate 9 was used to synthesize compound 169.

Intermediate 10: 3-chloro-4-iodo-N-methylpyridin-2-amine

A pressure tube was loaded with methylamine (25.0 mL, 50.1 mmol) (2M in THF), 3-chloro-2-fluoro-4-iodo-pyridine (4.3 g, 16.7 mmol) and DMSO (30 mL). Mixture was heated at 70° C. for 2 h. After cooling, H₂O (10 mL) was added and mixture extracted with EtOAc (2×50 mL). The organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified on silica gel (eluting with 0-20% EtOAc/Petroleum Ether) to give the title compound as a white solid (4.3 g, 96%). ¹H NMR (DMSO-d₆) δ 7.64 (m, 1H), 7.03 (m, 1H), 6.71 (bs, 1H), 2.82 (d, J=7.9 Hz, 3H). LCMS (ES⁺) m/z 269 (M+H)⁺; RT 1.37 min.

The intermediate 10 was used to synthesize compound 130 and the same procedure was used to synthesize the aminopyridines to obtain Examples 160, 161.

Intermediate 11: 2-ethylhexyl 3-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)propanoate

Step 1: 8-bromo-4-methyl-1,4-benzoxazin-3-one

8-bromo-4H-1,4-benzoxazin-3-one (300 mg, 1.32 mmol) was dissolved in DMF (6.5 mL) and treated with dipotassium carbonate (545 mg, 3.95 mmol) and iodomethane (0.12 mL, 1.97 mmol). The mixture was stirred at rt for 12 h then was diluted with EtOAc and the organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (271 mg, 85%). LCMS (ES⁺) m/z 242-244 (M+H)⁺, RT 1.51 min.

Step 2: 2-ethylhexyl 3-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)propanoate

A solution of 8-bromo-4-methyl-1,4-benzoxazin-3-one (111 mg, 0.460 mmol), Pd₂(dba)₃ (21 mg, 0.020 mmol), Xantphos (26.5 mg, 0.050 mmol), 2-ethylhexyl 3-sulfanylpropanoate (0.11 mL, 0.500 mmol) and DIPEA (0.16 mL, 0.920 mmol) in 1,4-dioxane (2.3 mL, 0.027 mol) was heated at 110° C. for 1 h. The resulting suspension was filtered through a pad of solka floc and the solvent was concentrated. Purification by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether) gave the title compound as a yellow oil (120 mg, 55%). LCMS (ES⁺) m/z 380 (M+H)⁺, RT 2.44 min.

The Intermediate 11 was used to synthesize compound 173.

Intermediate 12: 2-ethylhexyl 3-((3-methoxypyridin-4-yl)thio)propanoate

Step 1: 2-ethylhexyl 3-((3-methoxypyridin-4-yl)thio)propanoate

A solution of 4-bromo-3-methoxy-pyridine (88 mg, 0.470 mmol), Pd₂(dba)₃ (21.4 mg, 0.020 mmol), Xantphos (27 mg, 0.050 mmol), 2-ethylhexyl 3-sulfanylpropanoate (0.12 mL, 0.510 mmol) and DIPEA (0.16 mL, 0.940 mmol) in 1,4-dioxane (1 mL) was heated at 110° C. for 2 h. The mixture was concentrated in vacuo and the crude material dissolved in DCM and the organic phase was washed with NaHCO₃ saturated solution, dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (110 mg, 53%, 75% pure). LCMS (ES⁺) m/z 326 (M+H)⁺, RT 1.67 min.

The intermediate 12 was used to synthesize compounds 177, 182.

Intermediate 13: 2-ethylhexyl 3-((2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)thio)propanoate

Same procedure reported for the synthesis of Intermediate 12 was used using appropriate reagents.

The title compound was obtained as a yellow solid (60%, 90% pure). LCMS (ES⁺) m/z 352 (M+H)⁺, RT 2.3 min.

The Intermediate 13 was used to synthesize compound 178.

Intermediate 14: 3-ethoxy-4-iodopyridine

4-iodo-3-hydroxypyridine (50 mg, 0.230 mmol) and K₂CO₃ (47 mg, 0.340 mmol) were dissolved in DMF (1.8 mL, 0.019 mol) and iodoethane (0.02 mL, 0.230 mmol) was added. The mixture was stirred at 20° C. for 4 h then EtOAc was added and the organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-25% EtOAc in Petroleum Ether) gave the title compound as a colorless oil (27 mg, 48%). ¹H NMR (DMSO-d₆) δ 8.23 (s, 1H), 7.84 (m, 2H), 4.23 (q, J=8 Hz, 2H), 1.39 (t, J=8 Hz, 3H). LCMS (ES⁺) m/z 250 (M+H)⁺, RT 1.15 min.

The Intermediate 14 was used to synthesize compound 200.

Intermediate 15: 4-iodo-2-(methylamino)nicotinonitrile

Same procedure reported for the synthesis of intermediate 10 was used using appropriate reagents. The residue was purified on silica gel (eluting with 0-10% EtOAc/Petroleum Ether) to give the title compound as a white solid (34%). LCMS (ES⁺) m/z 260 (M+H)⁺; RT 1.43 min.

The Intermediate 15 was used to synthesize compound 201.

Intermediate 16: 3-bromo-N,N-dimethylpyridin-2-amine

Same procedure reported for the synthesis of intermediate 10 was used using appropriate reagents. The residue was purified on silica gel (eluting with 0-15% EtOAc/Petroleum Ether) to give the title compound as a colorless oil (74%, 90% pure). LCMS (ES⁺) m/z 201-203 (M+H)⁺; RT 1.34 min.

The Intermediate 16 was used to synthesize compound 211.

Intermediate 17: 2-amino-4-iodonicotinonitrile

Same procedure reported for the synthesis of Intermediate 10 was used using appropriate reagents. The residue was purified by flash chromatography on silica gel (eluting with 0-50% EtOAc/Petroleum Ether) to give the title compound as a yellow solid (36%). LCMS (ES⁺) m/z 246 (M+H)⁺; RT 1.13 min.

The Intermediate 17 was used to synthesize compound 215.

Intermediate 18: 2-(benzyloxy)-5-bromoquinoxaline

A solution of phenylmethanol (96 uL, 0.920 mmol), 5-bromanyl-2-chloranyl-quinoxaline (150 mg, 0.620 mmol) and dipotassium carbonate (128 mg, 0.920 mmol) in DMF (3 mL, 0.039 mol) was stirred at 70° C. for 13 h. H₂O was then added and mixture extracted with EtOAc. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-5% EtOAc in Petroleum Ether) gave the title compound as a yellow solid (155 mg, 80%). LCMS (ES⁺) m/z 315-317 (M+H)⁺, RT 2.37 min. The Intermediate 18 was used to synthesize compound 216, wherein in the final step of deprotection according to Scheme 18, the benzyloxy group is removed.

Intermediate 19: 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-one

A solution of pyrido[1,2-a]pyrimidin-4-one (200 mg, 1.37 mmol) and 1-bromopyrrolidine-2,5-dione (244 mg, 1.37 mmol) in acetic acid (3.7 mL) was stirred at rt for 2 h. Water was then added and mixture extracted with EtOAc. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound as a yellow solid (276 mg, 90%). ¹H NMR (DMSO-d₆) δ 9.02 (d, J=8 Hz, 1H), 8.68 (s, 1H), 8.03 (t, J=4 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.48 (t, J=4 Hz, 1H). LCMS (ES⁺) m/z 225-227 (M+H)⁺, RT 0.91 min.

The Intermediate 19 was used to synthesize compound 221.

Intermediate 20: 3-iodo-N-methylpicolinamide

3-iodopyridine-2-carboxylic acid (150 mg, 0.600 mmol) was dissolved in THE (2.4 mL) and CDI (147 mg, 0.9 mmol) followed by methanamine (2M in THF, 0.45 mL, 0.9 mmol) were added. The mixture was stirred at rt for 12 h. Water was then added and mixture extracted with DCM. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo.

Purification by flash chromatography (gradient elution 0-50% EtOAc in Petroleum Ether) gave the title compound as a yellow solid (77 mg, 49%). ¹H NMR (DMSO-d₆) δ 8.56 (d, J=4 Hz, 1H), 8.51 (bs, 1H), 8.37 (d, J=8 Hz, 1H), 7.25 (dd, J1=4 Hz, J2=8 Hz, 1H), 2.77 (d, J=8 Hz, 3H). LCMS (ES⁺) m/z 263 (M+H)⁺, RT 0.74 min.

The Intermediate 20 was used to synthesize compound 224.

Intermediate 21: 3-bromo-2-(pyrrolidin-1-yl)pyridine

A solution of pyrrolidine (192 uL, 2.34 mmol) and 3-bromo-2-chloro-pyridine (150 mg, 0.780 mmol) in DMSO (3 mL) was stirred at 70° C. for 12 h. H₂O was then added and mixture extracted with EtOAc. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution 0-15% EtOAc in Petroleum Ether) gave the title compound as a colorless oil (150 mg, 85%). LCMS (ES⁺) m/z 227-229 (M+H)⁺, RT 1.11 min.

The Intermediate 21 was used to synthesize compound 225.

Intermediate 22: 2-ethylhexyl 3-((3-oxo-2-(tetrahydro-2H-pyran-2-yl)-2,3-dihydropyridazin-4-yl)thio)propanoate

Step 1: 4-bromo-2-(oxan-2-yl)pyridazin-3-one

4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1 g, 2.96 mmol) was dissolved in diglyme (3 mL) and treated with NaBH₄ (201 mg, 5.33 mmol) at 0° C. The resulting solution was left to rt overnight. Water was added and the reaction mixture was directly purified by reverse phase chromatography (gradient elution 0-60% MeCN in H₂O). After removal of volatiles the aqueous phase was washed with DCM and lyophilized to get the title compound as a white solid (277 mg, 36%). LCMS (ES⁺) m/z 259-261 (M+H)⁺, RT 1.11 min.

Step 2: 2-ethylhexyl 3-((3-oxo-2-(tetrahydro-2H-pyran-2-yl)-2,3-dihydropyridazin-4-yl)thio)propanoate

Same procedure reported for the synthesis of Intermediate 12 was used using appropriate reagents. The title compound was obtained as a yellow oil (122 mg, 81%). ¹H NMR (DMSO-d₆) δ 7.83 (d, J=4 Hz, 1H), 7.20 (d, J=4 Hz, 1H), 5.87 (dd, J₁=4 Hz, J₂=12 Hz, 1H), 3.97-3.90 (m, 3H), 3.61-3.65 (m, 1H), 3.12 (t, J=8 Hz, 2H), 2.73 (t, J=8 Hz, 2H), 2.15-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.72-1.45 (m, 5H), 1.33-1.20 (m, 8H), 0.85-0.82 (m, 6H). LCMS (ES⁺) m/z 397 (M+H)⁺, RT 2.32 min.

The Intermediate 22 was used to synthesize compound 234.

Intermediate 23: 2-ethylhexyl 3-((2-(oxazol-2-ylmethoxy)pyridin-3-yl)thio)propanoate

Step 1: 2-[(3-iodopyridin-2-yl)oxymethyl]-1,3-oxazole

A mixture of 3-iodo-1H-pyridin-2-one (70 mg, 0.320 mmol) and K₂CO₃ (66 mg, 0.480 mmol) was stirred in DMF (0.8 mL) for 30 min at 20° C. 2-Chloromethyl-oxazole (37 mg, 0.320 mmol) was added and the mixture was stirred at 80° C. for 1.5 h. After removal of solvent the residue was dissolved in EtOAc and the solution filtered on a pad of solca floc. The filtrates were concentrated in vacuo and the residue purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether) affording the title compound as a colorless oil (79 mg, 83%). LCMS (ES⁺) m/z 303 (M+H)⁺, RT 0.93 min.

Step 2: 2-ethylhexyl 3-((2-(oxazol-2-ylmethoxy)pyridin-3-yl)thio)propanoate

Same procedure reported for the synthesis of Intermediate 12 was used using appropriate reagents. The title compound was obtained as a yellow oil (30 mg, 46%). LCMS (ES⁺) m/z 393 (M+H)⁺, RT 2.1 min.

The Intermediate 23 was used to synthesize compound 235.

Intermediate 24: 2-ethylhexyl 3-((3-methoxypyridazin-4-yl)thio)propanoate

Same procedure reported for the synthesis of Intermediate 12 was used using appropriate reagents. The title compound was obtained as a colorless oil (99%). LCMS (ES⁺) m/z 327 (M+H)⁺, RT 1.65 min.

The Intermediate 24 was used to synthesize compound 236.

Intermediate 25: potassium 4-methoxypyridine-3-thiolate

Step 1: 2-ethylhexyl 3-(4-methoxypyridin-3-yl)sulfanylpropanoate

Same procedure reported for the synthesis of intermediate 12 was used using appropriate reagents The title compound was obtained as a yellow oil (92%). LCMS (ES⁺) m/z 326 (M+H)⁺, RT 1.63 min

Step 2: potassium 4-methoxypyridine-3-thiolate

A solution of 2-ethylhexyl 3-(4-methoxypyridin-3-yl)sulfanylpropanoate (70 mg, 0.220 mmol) in THE (0.8 mL) was treated at −78° C. with potassium 2-methylpropan-2-olate (48 mg, 0.430 mmol).

The reaction mixture was stirred at −78° C. for 2 h and at rt for additional 3 h. The reaction mixture was quenched with H₂O and concentrated under reduced pressure. The aqueous phase was extracted with EtOAc. The organic layers were discarded and the aqueous phase was concentrated under reduced pressure. The title compound was obtained as a creamy solid (99%).

The Intermediate 25 was used to synthesize compound 237.

Intermediate 26: 4-bromo-5-chloropyridin-2-ol

Step 1: 4-bromo-5-chloropyridin-2-ol

4-bromo-5-chloro-2-methoxy-pyridine (25 mg, 0.110 mmol) was dissolved in DCM (0.9 mL) and treated dropwise with tribromoborane (0.22 mL, 0.220 mmol) at −78° C. The mixture was stirred for 12 h at rt and for additional 12 h at 55° C. Water and MeOH were carefully added to the mixture and the solution was extracted with EtOAc. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound was obtained as a pink powder (20 mg, 85%). ¹H NMR (DMSO-d₆) δ 7.86 (s, 1H), 6.91 (s, 1H). LCMS (ES⁺) m/z 208-210 (M+H)⁺, RT 0.99 min.

The Intermediate 26 was used to synthesize compound 241.

Intermediate 27: 3-chloro-N-ethyl-4-iodopyridin-2-amine

The same procedure reported for the synthesis of Intermediate 10 was used using appropriate reagents. The residue was purified on silica gel (eluting with 0-30% EtOAc/Petroleum Ether) to give the title compound as a white solid (90%). LCMS (ES⁺) m/z 283 (M+H)⁺; RT 1.73 min.

The Intermediate 27 was used to synthesize compound 246.

Intermediate 28: 2-((5-bromo-6-methoxypyridin-3-yl)methyl)isoindoline-1,3-dione

Step 1: (5-bromo-6-methoxy-pyridin-3-yl)methanol

A solution of 5-bromo-6-methoxy-pyridine-3-carboxylic acid (300 mg, 1.29 mmol) in THE (3 mL) was treated with CDI (335 uL, 1.94 mmol). The mixture was stirred at rt for 1 h. A solution of NaBH₄ (245 mg, 6.46 mmol) in H₂O (3 ml) was added dropwise at 0° C. and stirred at this temperature for 30 min. HCl 2M (3 mL) was added dropwise and the resulting mixture stirred for 30 minutes at rt. Mixture was poured into NaHCO₃ saturated solution (6 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash chromatography (gradient elution 0-50% EtOAc in Petroleum Ether) to afford the title compound as a white solid (232 mg, 82%). LCMS (ES⁺) m/z 218-220 (M+H)⁺, RT 1.13 min.

Step 2: 2-((5-bromo-6-methoxypyridin-3-yl)methyl)isoindoline-1,3-dione

A solution of triphenylphosphine (258 mg, 0.980 mmol), (5-bromanyl-6-methoxy-pyridin-3-yl)methanol (195 mg, 0.890 mmol) and phthalimide (145 mg, 0.980 mmol) in THE (3 mL) was treated with diethyl (E)-1,2-diazenedicarboxylate (179 uL, 0.980 mmol). The mixture was stirred 1 h at rt then concentrated in vacuo and purified by flash chromatography (gradient elution 0-50% EtOAc in Petroleum Ether) to afford the title compound as a white solid (330 mg, 83%). LCMS (ES⁺) m/z 347-349 (M+H)⁺, RT 1.91 min.

The Intermediate 28 was used to synthesize compound 250.

Intermediate 29: 7-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine

Step 1: 7-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine

A solution of iodomethane (189 uL, 3.03 mmol), 7-bromo-2H-pyrazolo[4,3-b]pyridine (400 mg, 2.02 mmol) and dipotassium carbonate (558 mg, 4.04 mmol) in DMF (6 mL) was stirred at rt for 12 h. NH₄Cl saturated solution (5 mL) was added dropwise and mixture extracted with EtOAc (3×20 mL). Organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash chromatography (gradient elution 0-70% EtOAc in Petroleum Ether) to afford the title compound as a white solid (215 mg, 50%). ¹H NMR (DMSO-d₆) δ 8.36 (s, 1H), 8.33 (d, J=4 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 4.34 (s, 3H). LCMS (ES⁺) m/z 212-214 (M+H)⁺, RT 1.15 min.

The Intermediate 29 was used to synthesize compound 261.

Intermediate 30: 2-ethylhexyl 3-((6-(bis(tert-butoxycarbonyl)amino)-2-methoxypyridin-3-yl)thio)propanoate

Step 1: tert-butyl N-(5-bromanyl-6-methoxy-pyridin-2-yl)-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

A solution of 5-bromo-6-methoxy-pyridin-2-amine (200 mg, 0.990 mmol) and tert-butoxycarbonyl tert-butyl carbonate (537 mg, 2.46 mmol) in THE (5 mL) was treated with [bis(trimethylsilyl)amino]sodium (2.46 mL, 2.46 mmol) at 0° C. The mixture was left warming to rt and stirred at this temperature for 18 h. Reaction mixture was poured into brine and extracted with EtOAc (3×20 mL). The combined organics were washed with H₂O, brine, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash chromatography (gradient elution 0-10% EtOAc in Petroleum Ether) to afford the title compound as a yellow solid (255 mg, 64%). LCMS (ES⁺) m/z 403-405 (M+H)⁺, RT 2.37 min.

Step 2: 2-ethylhexyl 3-((6-(bis(tert-butoxycarbonyl)amino)-2-methoxypyridin-3-yl)thio)propanoate

Same procedure reported for the synthesis of intermediate 12 was used using appropriate reagents. The title compound was obtained as a yellow oil (65 mg, 24%). LCMS (ES⁺) m/z 541 (M+H)⁺, RT 2.45 min.

The Intermediate 30 was used to synthesize compound 269.

Intermediate 31: 3-chloro-N-cyclopropyl-4-iodopyridin-2-amine

Step 1: 3-chloro-N-cyclopropyl-4-iodopyridin-2-amine

Same procedure reported for the synthesis of intermediate 10 was used using appropriate reagents. The residue 196 was purified on silica gel (eluting with 0-20% EtOAc in Petroleum Ether) to give the title compound as a white solid (79%). LCMS (ES⁺) m/z 295 (M+H)⁺; RT 1.41 min.

The Intermediate 31 was used to synthesize compounds 160, 161, 174, 189, 196, 197.

Intermediate 32: 2-ethylhexyl 3-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)propanoate

Step 1: 2-ethylhexyl 3-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)propanoate

Same procedure reported for the synthesis of Intermediate 12 was used using appropriate reagents. The title compound was obtained as a yellow solid (61%, 80% pure).

The Intermediate 32 was used to synthesize compound 184.

Intermediate 33: (R)—N—((S)-5-fluoro-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

The compound was prepared according to Scheme 27, following the procedures reported below.

Step 1: 1-(tert-butyl) 4-ethyl 4-(4-fluoro-3-methoxybenzyl)piperidine-1,4-dicarboxylate

1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (1.43 mL, 5.83 mmol) was dissolved in THF (30 mL) and (diisopropylamino)lithium (4.37 mL, 8.74 mmol) 2 M in THF was added at −70° C. After stirring for 1 h at this temperature, 4-(bromomethyl)-1-fluoranyl-2-methoxy-benzene (1.28 g, 5.83 mmol), dissolved in THE (5 mL), was added dropwise. The resulting solution was stirred at −70° C. for 3 h and then quenched with NH₄Cl saturated solution. EtOAc was added to the mixture, the aqueous layer was separated, and the organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The title compound was obtained as an orange oil (2.3 g, 100%). LCMS (ES⁺) m/z 396 (M+H)⁺, RT 2.3 min.

Step 2: 1-(tert-butoxycarbonyl)-4-(4-fluoro-3-methoxybenzyl)piperidine-4-carboxylic acid

1-(tert-butyl) 4-ethyl 4-(4-fluoro-3-methoxybenzyl)piperidine-1,4-dicarboxylate (2.3 g, 5.82 mmol) was dissolved in methanol (20 mL) and treated with a solution of NaOH (1.4 g, 34.9 mmol) in H₂O (12 mL). The mixture was stirred at 75° C. for 3 days, then taken up in EtOAc and washed with H₂O and brine. The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow powder (1.94 g, 91%). LCMS (ES⁻) m/z 366 (M−H)⁻, RT 1.88 min.

Step 3: tert-butyl 6-fluoro-5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

1-(tert-butoxycarbonyl)-4-(4-fluoro-3-methoxybenzyl)piperidine-4-carboxylic acid (1.0 g, 2.72 mmol) was charged in a flask and polyphosphoric acid (3.34 mL, 68.06 mmol) was dropped on it. The slurry was heated at 120° C. for 30 min. Ice was dropped in the flask and the pH was adjusted to 10 with 2N NaOH. The mixture was then treated with tert-butoxycarbonyl tert-butyl carbonate (653 mg, 2.99 mmol) and stirred at rt for 2 h. DCM was added to the mixture, the organic phase was washed with brine, dried over Na₂SO₄, filtered, concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether) to afford the title compound as a pale yellow powder (425 mg, 45%). LCMS (ES⁺) m/z 350 (M+H)⁺, RT 1.99 min.

Step 4: tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl 6-fluoro-5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (100 mg, 0.290 mmol) in TiOEt₄ (0.9 mL, 4.29 mmol) was heated at 90° C. for 30 minutes. 2-methylpropane-2-sulfinamide (0.1 g, 0.860 mmol) was added and the mixture stirred at 900 for 24 h. After cooling down, the mixture was poured in EtOAc (400 mL) and brine (300 mL) was added. The slurry was stirred for 15 minutes and filtered. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil which was used as crude. LCMS (ES⁺) m/z 453 (M+H)⁺, RT 2.18 min.

Step 5: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (130 mg, 0.290 mmol) in THE (1.2 mL) was cooled at −50° C. NaBH₄ (16.3 mg, 0.430 mmol) was added portionwise and the resulting mixture was left stirring at rt for 16 h. EtOAc (400 mL) was then added and the mixture washed with H₂O and brine, dried over Na₂SO₄, filtered, concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-70% EtOAc in Petroleum Ether) to afford the title compound as a white powder (73 mg, 56%). LCMS (ES⁺) m/z 455 (M+H)⁺, RT 2.07 min.

Step 6: (R)—N—((S)-5-fluoro-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 33)

tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (78 mg, 0.170 mmol) was dissolved in DCM (1 mL) then TFA (0.2 mL) was added. The reaction mixture was stirred at rt for 2 h then was concentrated in vacuo to afford the title compound as a crude. LCMS (ES⁺) m/z 355 (M+H)⁺, RT 1.07 min.

Intermediate 33 was used for the synthesis of Examples 186.

Intermediate 34: (R)—N—((S)-5-(hydroxymethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

The compound was prepared according to Scheme 28, following the procedures reported below.

Step 1: tert-butyl 6-(((4-methoxybenzyl)oxy)methyl)-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A pressure vial was loaded with tert-butyl 5-bromanyl-3-oxidanylidene-spiro[1H-indene-2,4′-piperidine]-1′-carboxylate (500 mg, 1.31 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (61 mg, 0.130 mmol), potassium trifluoro{[(4-methoxybenzyl)oxy]methyl}borate (407 mg, 1.58 mmol), Pd(OAc)₂ (15 mg, 0.070 mmol) and dicesium carbonate (1.29 g, 3.94 mmol). The mixture was degassed and 1,4-dioxane (4.5 mL, 0.053 mol) and H₂O (0.450 mL, 0.025 mol) were added and resulting mixture was stirred in a preheated oil bath at 100° C. for 24 h. NH₄Cl saturated solution (3 mL) was added and the mixture extracted with EtOAc (3×15 mL). Combined organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-30% EtOAc in Petroleum Ether) to afford the title compound as yellow solid (285 mg, 48%). LCMS (ES⁺) m/z 452 (M+H)⁺, RT 2.32 min.

Step 2: tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-(((4-methoxybenzyl)oxy)methyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 4 was followed using appropriate reagents. The residue was purified on silica gel (eluting with 0-40% EtOAc+5% MeOH/Petroleum Ether) to give the title compound as a white solid (178 mg, 51%). LCMS (ES⁺) m/z 555 (M+H)⁺, RT 2.45 min.

Step 3: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(((4-methoxybenzyl)oxy)methyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 5 was followed using appropriate reagents. The residue was purified on silica gel (eluting with 0-50% EtOAc in Petroleum Ether and then +5% MeOH/EtOAc in Petroleum Ether) to give the title compound as a white solid (119 mg, 67%). LCMS (ES⁺) m/z 557 (M+H)⁺, RT 2.38 min.

Step 4: (R)—N—((S)-5-(hydroxymethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 34)

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 6 was followed using appropriate reagents. The residue was used as a crude. LCMS (ES⁺) m/z 337 (M+H)⁺, RT 0.79 min.

Intermediate 34 was used for the synthesis of Example 244.

Intermediate 35: (R)—N—((S)-5-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

The compound was prepared according to Scheme 29, following the procedures reported below.

Step 1: tert-butyl 6-cyclopropyl-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of intermediate 34 in Scheme 28 step 1 was followed using appropriate reagents. The residue was purified on silica gel (eluting with 0-15% EtOAc in Petroleum Ether) to give the title compound as a yellow oil (70 mg, 52%). ¹H NMR (CDCl₃) δ 7.43-7.35 (m, 3H), 4.15-4.11 (m, 2H), 3.00-2.97 (m, 4H), 1.94-1.82 (m, 3H), 1.49 (s, 9H), 1.37 (d, J=16 Hz, 2H), 1.01 (d, J=8 Hz, 2H), 0.73 (d, J=4 Hz, 2H). LCMS (ES⁺) m/z 342 (M+H)⁺, RT 2.31 min.

Step 2: tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of intermediate 33 in Scheme 27 step 4 was followed using appropriate reagents. The title compound was obtained as a white solid and used as a crude. LCMS (ES⁺) m/z 445 (M+H)⁺, RT 2.41 min.

Step 3: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of intermediate 33 in Scheme 27 step 5 was followed using appropriate reagents. The residue was purified on silica gel (eluting with 0-50% EtOAc/Petroleum Ether) to give the title compound as a white solid (52 mg, 43%). ¹H NMR (CDCl₃) δ 7.09 (d, J=8 Hz, 1H), 7.02 (s, 1H), 6.95 (d, J=8 Hz, 1H), 4.45 (d, J=8 Hz, 1H), 4.00 (br d, J=12 Hz, 2H), 3.54-3.50 (m, 1H), 3.01-2.89 (m, 3H), 2.63 (d, J=16 Hz, 1H), 1.92-1.88 (m, 1H), 1.85-1.52 (m, 2H), 1.46 (s, 9H), 1.30 (s, 9H), 1.26 (d, J=8 Hz, 2H), 0.96 (d, J=8 Hz, 2H), 0.66 (d, J=4 Hz, 2H). LCMS (ES⁺) m/z 447 (M+H)⁺, RT 2.36 min.

Step 4: (R)—N—((S)-5-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate 35)

Same procedure reported for the synthesis of intermediate 33 in Scheme 27 step 6 was followed using appropriate reagents. The residue was used as a crude. LCMS (ES⁺) m/z 347 (M+H)⁺, RT 1.19 min.

Intermediate 35 was used for the synthesis of Example 257.

Intermediate 36: 2-methyl-N—((R)-3H-spiro[furo[3,2-b]pyridine-2,4′-piperidin]-3-yl)propane-2-sulfinamide

Step 1: 2-(1,3-dithian-2-yl)-3-fluoro-pyridine

A solution of 3-fluoropyridine-2-carbaldehyde (1000 mg, 7.99 mmol) and propane-1,3-dithiol (0.88 mL, 8.79 mmol) in DCE (16 mL, 0.5 M) was treated with 4-methylbenzenesulfonic acid hydrate (152 mg, 0.8 mmol). The reaction mixture was stirred at reflux for 2 h and then taken up with DCM, washed with 1M NaOH aqueous solution and brine. The aqueous phase was back extracted with DCM (×2). The recombined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100%) to afford the title product (1.54 g; 89%) as a pale yellow liquid. LCMS (ES⁺) m/z 216 (M+H)⁺; RT 1.5 min.

Step 2: tert-butyl 4-[2-(3-fluoropyridin-2-yl)-1,3-dithian-2-yl]-4-oxidanyl-piperidine-1-carboxylate

A solution of 2-(1,3-dithian-2-yl)-3-fluoro-pyridine (1.45 g, 6.73 mmol) in THF (11 mL) was added to a stirred and degassed solution of (diisopropylamino)lithium (4.04 mL, 8.08 mmol, 2 M in THF/heptane) in THF (11 mL) cooled to −78° C. The reaction mixture was stirred at −20° C. (ice+brine bath) for 30 min then cooled to −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.34 g, 6.73 mmol) in THF (11 mL) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with brine, warmed up to RT and diluted with EtOAc. The slurry was filtered off and the organic phase was separated, washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product (1.35 g) was used in the next step without purification. LCMS (ES⁺) m/z 415 (M+H)⁺; RT 1.8 min.

Step 3: tert-butyl 4-(3-fluoropyridin-2-yl)carbonyl-4-oxidanyl-piperidine-1-carboxylate

Pyridinium tribromide (1562 mg, 4.88 mmol) and tetrabutylammonium bromide (104 mg, 0.33 mmol) were added to a stirred solution of tert-butyl 4-[2-(3-fluoropyridin-2-yl)-1,3-dithian-2-yl]-4-oxidanyl-piperidine-1-carboxylate (1.35 g, 3.26 mmol) and pyridine (0.53 mL, 6.51 mmol) in DCM (20 mL)/H₂O (4 mL). The reaction mixture was stirred at RT for 2 h and pyridinium bromide (500 mg), tetrabutylammonium bromide (20 mg) and 0.5 mL of pyridine. After 30 min under stirring the reaction mixture was diluted with DCM and washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100%) to afford the title product (0.64 g; 60%) as pale red sticky solid. LCMS (ES⁺) m/z 325 (M+H)⁺; RT 1.72 min.

Step 4: tert-butyl 3-oxidanylidenespiro[furo[3,2-b]pyridine-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl 4-(3-fluoranylpyridin-2-yl)carbonyl-4-oxidanyl-piperidine-1-carboxylate (640 mg, 1.97 mmol) in THE (11 mL, 0.18 M) was treated with a 1M solution of potassium 2-methylpropan-2-olate (2.96 mL, 2.96 mmol). The reaction mixture was stirred at 70° C. for 30 min and poured into ice water and extracted with EtOAc. The organic phases were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100%) to afford the title product (0.36 g; 42%) as yellow solid. LCMS (ES⁺) m/z 305 (M+H)⁺; RT 1.66 min.

Step 5, 6 and 7 were performed using the same procedures described, respectively, in steps 4, 5, 6 of Scheme 27. Intermediate 36 was used for the synthesis of Example 163, according to the procedure indicated in Scheme 18.

Intermediate 37: (R)—N—((S)-5-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

The compound was prepared according to Scheme 30, following the procedures reported below.

Step 1: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(hydroxymethyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(((4-methoxybenzyl)oxy)methyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (44 mg, 0.080 mmol) (prepared as reported in the synthesis of Intermediate 34, steps 1, 2, 3 in Scheme 28) in DCM (1 mL) and H₂O (0.300 mL) at 0° C. was treated with 4,5-dichloro-3,6-dioxo-cyclohexa-1,4-diene-1,2-dicarbonitrile (18 mg, 0.080 mmol). The mixture was stirred at rt for 2 h. NaHCO₃ saturated solution (3 mL) was added dropwise and mixture extracted with DCM (2×20 mL). Combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Crude material was dissolved in THE (1 mL) and treated with NaBH₄ (5.5 mg). Resulting mixture was stirred at rt for 1 h. Water (3 mL) was added dropwise and mixture extracted with DCM (2×20 mL). Combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-90% EtOAc in Petroleum Ether) to afford the title compound as a white solid (33 mg, 96%). LCMS (ES⁺) m/z 437 (M+H)⁺, RT 1.72 min.

Step 2: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(hydroxymethyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (33 mg, 0.080 mmol) in DCM (1 mL) at 0° C. was treated with NN-diethyl-1,1,1-trifluoro-λ⁴-sulfanamine (30 uL, 0.230 mmol). Resulting mixture was stirred at rt for 30 min. NaHCO₃ saturated solution (3 mL) was added dropwise and mixture extracted with DCM (2×20 mL). Combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified by flash chromatography (gradient elution 0-50% EtOAc in Petroleum Ether) to afford the title compound as a white solid (13 mg, 39%). LCMS (ES⁺) m/z 439 (M+H)⁺, RT 2.07 min.

Step 3: (R)—N—((S)-5-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

A solution of tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (13 mg, 0.030 mmol) in DCM (0.5 mL) at 0° C. was treated with TFA (0.2 mL). The mixture was stirred at rt for 1 h. Mixture was concentrated under reduced pressure and the residue was used as crude. LCMS (ES⁺) m/z 339 (M+H)⁺, RT 0.91 min.

Intermediate 37 was used for the synthesis of Example 245.

Intermediate 38: (R)—N—((S)-5-(hydroxymethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

Same procedure reported for the synthesis of intermediate 34 in Scheme 28 was followed using appropriate reagents. The residue was used as a crude. LCMS (ES⁺) m/z 337 (M+H)⁺, RT 0.86 min.

Intermediate 38 was used for the synthesis of Example 252.

Intermediate 39: 1-(3-chloro-4-iodopyridin-2-yl)azetidine-3-carbonitrile

A pressure tube was loaded with 3-chloro-2-fluoro-4-iodo-pyridine (200 mg, 0.780 mmol), azetidine-3-carbonitrile hydrochloride (184 mg, 1.55 mmol, DIPEA (0.3 mL, 1.71 mmol) and DMSO (3 mL). The mixture was heated at 70° C. for 3 h, then H₂O (5 mL) was added and extracted with EtOAc (2×20 mL). The organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with EtOAc from 0% to 100% in Petroleum Ether) to afford the title product (167 mg; 67%). LCMS (ES⁺) m/z 320 (M+H)⁺; RT 1.76 min.

The intermediate 39 was used to synthesize compound 191.

Intermediate 40: 5-bromo-6-chloro-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

The compound was prepared according to Scheme 31, following the procedures reported below.

A solution of 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (prepared as reported in the synthesis of example 107, step 1, Scheme 6; 400 mg, 1.86 mmol) in DCE (8.5 mL) was treated with 1-chloropyrrolidine-2,5-dione (248 mg, 1.86 mmol) and the mixture heated at 75° C. for 18 h. After cooling to rt the mixture was concentrated in vacuo and the residue purified by reverse phase chromatography (gradient elution 0-100% CH₃CN+0.01% TFA in H₂O+0.01% TFA) to afford the title compound as a beige solid (410 mg, 88%). LCMS (ES⁺) m/z 248-250 (M+H)⁺, RT 1.08 min.

Intermediate 40 was used for the synthesis of Example 259.

Intermediate 41: 4-(3-chloro-4-iodopyridin-2-yl)morpholine

The compound was prepared using the same procedure indicated for the synthesis of Intermediate 39, by using morpholine instead of azetidine-3-carbonitrile hydrochloride.

Intermediate 41 was used for the synthesis of Example 180.

Intermediate 42: 3-chloro-4-iodo-2-(3-methoxyazetidin-1-yl)pyridine

The compound was prepared using the same procedure indicated for the synthesis of Intermediate 39, by using 3 methoxy-azetidine hydrochloride instead of azetidine-3-carbonitrile hydrochloride.

Intermediate 42 was used for the synthesis of Example 181.

Intermediate 43: (R)—N—((S)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide & (R)—N—((R)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide

The compound was prepared according to Scheme 32, following the procedures reported below.

Step 1: (3-bromo-5-fluoropyridin-2-yl)methyl methanesulfonate

A solution of (3-bromo-5-fluoropyridin-2-yl)methanol (2 g, 9.71 mmol) and TEA (2.69 mL, 19.42 mmol) in DCM (26 mL) cooled at −15° C. was treated with methanesulfonyl chloride (0.83 mL, 10.68 mmol). The mixture was stirred at −15° C. for 1 h and then treated with H₂O. The organic phase was separated, washed with brine, dried over Na₂SO₄ and evaporated in vacuo to get the title compound as a yellow oil which was used as a crude in the next step. ¹H NMR (CDCl₃) δ 8.48 (d, J=4 Hz, 1H), 7.73 (dd, J₁=4 Hz, J₂=8 Hz, 1H), 5.46 (s, 2H), 3.13 (s, 3H); LCMS (ES⁺) m/z 284-286 (M+H)⁺, RT 1.32 min.

Step 2: 1-(tert-butyl) 4-ethyl 4-((3-bromo-5-fluoropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate

A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (3.1 mL, 12.62 mmol) in THE (12 mL) cooled to −50° C. was treated with (diisopropylamino)lithium (7.8 mL, 15.53 mmol; 2M solution in THF) and the mixture stirred for 1 h at this temperature. A solution of (3-bromo-5-fluoropyridin-2-yl)methyl methanesulfonate (2.76 g, 9.71 mmol) in THE (5 mL) was slowly added and the reaction mixture was allowed to reach rt and stirred for further 30 min. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc. Organic phase was separated, washed with brine, dried over Na₂SO₄ and concentrated in vacuo to get a residue which was purified on silica gel (eluting with 5-50% EtOAc/Petroleum Ether) to give the title compound as a white solid (3.96 g, 92%). ¹H NMR (CDCl₃) δ 8.33 (d, J=4 Hz, 1H), 7.61 (dd, J₁=4 Hz, J₂=8 Hz, 1H), 4.16 (q, J=8 Hz, 2H), 3.83 (br d, J=12 Hz, 2H), 3.24 (s, 2H), 3.01 (br t, J=12 Hz, 2H), 2.13 (br d, J=12 Hz, 2H), 1.61-1.58 (m, 2H), 1.45 (s, 9H), 1.21 (t, J=8 Hz, 3H); LCMS (ES⁺) m/z 445-447 (M+H)⁺, RT 2.41 min

Step 3: 4-((3-bromo-5-fluoropyridin-2-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

A solution of 1-(tert-butyl) 4-ethyl-4-((3-bromo-5-fluoropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate (1.5 g, 3.37 mmol) in 1,4-dioxane (8.4 mL, 0.099 mol) was treated with a solution of NaOH (1.35 g, 33.7 mmol) in H₂O (2.8 mL) and the mixture was stirred at 120° C. for 24 h. After cooling to rt the mixture was diluted with EtOAc. The unsoluble material was filtered off, aqueous phase was separated and the organic phase was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to get a residue which was purified on silica gel (eluting with 0-20% MeOH in DCM) to give the title compound as a white solid (960 mg, 68%). ¹H NMR (DMSO-d₆) δ 12.49 (br s, 1H), 8.53 (d, J=4 Hz, 1H), 8.17 (dd, J₁=4 Hz, J₂=8 Hz, 1H), 3.68 (br d, J=12 Hz, 2H), 3.15 (s, 2H), 2.92 (br s, 2H), 1.96 (br d, J=12 Hz, 2H), 1.45 (br t, J=8 Hz, 2H), 1.37 (s, 9H); LCMS (ES⁺) m/z 417-419 (M+H)⁺, RT 1.91 min

Step 4: tert-butyl 4-((3-bromo-5-fluoropyridin-2-yl)methyl)-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

A solution of 4-((3-bromo-5-fluoropyridin-2-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (650 mg, 1.56 mmol), HATU (1185 mg, 3.12 mmol), DIPEA (2.71 mL, 15.58 mmol) and N-methoxymethanamine hydrochloride (608 mg, 6.23 mmol) in DMF (8 mL) was stirred at 50° C. for 48 h. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuo to get a residue which was purified on silica gel (eluting with 10-100% EtOAc/Petroleum Ether) to give the title compound as a pale yellow solid (470 mg, 66%). ¹H NMR (DMSO-d₆) δ 8.52 (d, J=4 Hz, 1H), 8.13 (dd, J₁=4 Hz, J₂=8 Hz, 1H), 3.68 (br d, J=12 Hz, 2H), 3.63 (s, 3H), 3.09 (s, 3H), 2.96 (br s, 2H), 2.07 (br d, J=12 Hz, 2H), 1.49 (br t, J=8 Hz, 2H), 1.38 (s, 9H); LCMS (ES⁺) m/z 460-462 (M+H)⁺, RT 2.14 min

Step 5: tert-butyl 3-fluoro-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate

A solution of tert-butyl 4-((3-bromo-5-fluoropyridin-2-yl)methyl)-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (470 mg, 1.02 mmol) in THE (3.40 mL) at −70° C. was treated with nBuLi (0.61 mL, 1.53 mmol; 2.5 M sol in hexane) and stirred at this temperature for 30 min. The reaction mixture was treated with saturated aqueous NH₄Cl solution and diluted with EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to get a residue which was purified on silica gel (eluting with 10-100% EtOAc/Petroleum Ether) to give the title compound as a pale yellow solid (280 mg, 86%). ¹H NMR (DMSO-d₆) δ 8.91 (d, J=4 Hz, 1H), 7.98 (dd, J₁=4 Hz, J₂=8 Hz, 1H), 3.93 (br d, J=12 Hz, 2H), 3.18 (s, 2H), 3.00 (br s, 2H), 1.66-1.62 (m, 2H), 1.52-1.48 (m, 2H), 1.42 (s, 9H); LCMS (ES⁺) m/z 321 (M+H)⁺; RT 1.79 min

Step 6: tert-butyl (R)-5-((tert-butylsulfinyl)imino)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 4 was used using appropriate reagents and THE as solvent. The residue was purified on silica gel (eluting with 10-100% EtOAc/Petroleum Ether) to give the title compound as a yellow solid (450 mg, 95%). LCMS (ES⁺) m/z 424 (M+H)⁺, RT 2.05 min.

Step 7: tert-butyl (S)-5-(((R)-tert-butylsulfinyl)amino)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate & tert-butyl (R)-5-(((R)-tert-butylsulfinyl)amino)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 5 was used using appropriate reagents. The residue was purified on silica gel (eluting with 0-20% MeOH/DCM) to give the title compound as a yellow solid as a mixture of diasteroisomers (ratio 55:4; 147 mg, 33%). LCMS (ES⁺) m/z 426 (M+H)⁺, RT 2.75-2.87 min.

Step 8: (R)—N—((S)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide & (R)—N—((R)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide

Same procedure reported for the synthesis of Intermediate 33 in Scheme 27 step 6 was used using appropriate reagents. The title compounds were obtained in a ratio 60:40. The residue was used as a crude.

Intermediate 43 was used for the synthesis of Examples 229 and 230.

Intermediate 44: 2-methyl-N-(2-methylspiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-4-yl)propane-2-sulfinamide

Step 1: 1-methyl-5,6-dihydrocyclopenta[c]pyrazol-4-one and 2-methyl-5,6-dihydrocyclopenta[c]pyrazol-4-one

A solution of iodomethane (458 uL, 7.37 mmol), 5,6-dihydro-1H-cyclopenta[c]pyrazol-4-one (750 mg, 6.14 mmol) and dipotassium carbonate (1.27 g, 9.21 mmol) in DMF (18 mL, 0.3 M) under nitrogen was stirred at 50° C. for 12 h. H₂O (10 mL) was added dropwise and the mixture was extracted with EtOAc (2×50 mL). The organic phase was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100%) to give the title compound (895 mg; 83%) as a 60:40 mixture of regioisomers by ¹H NMR. ¹H NMR δ ppm (400 MHz, DMSO-d₆): 7.65 (1H, s), 7.16 (0.7H, s), 3.45 (3H, s), 2.87 (2.2H, s), 2.45-2.42 (2H, m), 2.39-2.36 (2H, m), 2.07-2.04 (2.9H, m).

Step 2: 1-methyl-1′-(phenylmethyl)spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-4-one and 2-methyl-1′-(phenylmethyl)spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-4-one

A solution of a mixture of 2-methyl-5,6-dihydrocyclopenta[c]pyrazol-4-one and 1-methyl-5,6-dihydrocyclopenta[c]pyrazol-4-one (600 mg, 4.41 mmol) in DMF (8.5 mL, 0.5 M) under nitrogen was treated with sodium hydride (352 mg, 8.81 mmol; 60% in mineral oil) portionwise. The resulting mixture was stirred at rt for 1 h. 2-bromo-N-(2-bromoethyl)-N-(phenylmethyl) ethanamine (1.56 g, 4.85 mmol) was added dropwise and the mixture was stirred at 60° C. for 6 h. After cooling to rt, the reaction mixture was quenched with H₂O (5 mL) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material (300 mg) was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100% and then till 5% MeOH in EtOAc) to afford the title compounds as a regioisomeric mixture 75:25 (120 mg, 9%) as a brown solid. LCMS (ES⁺) m/z 296 (M+H)⁺; RT 0.65 and 0.76 min.

Step 3: tert-butyl 1-methyl-4-oxidanylidene-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and tert-butyl 2-methyl-4-oxidanylidene-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate

A solution of 1-methyl-1′-(phenylmethyl)spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-4-one and 2-methyl-1′-(phenylmethyl)spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-4-one (180 mg, 0.61 mmol) in DCE (2 mL) was treated at 0° C. under nitrogen with 1-chloroethyl carbonochloridate (105 uL, 1.07 mmol) dropwise. The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was dissolved in MeOH (4 mL) and stirred at 80° C. for 1 h, then concentrated and taken up in DCM (4 mL). DIPEA (0.32 mL, 1.83 mmol) and tert-butoxycarbonyl tert-butyl carbonate (199 mg, 0.91 mmol) were added and the mixture stirred at rt for 1 h, then concentrated under reduced pressure and the crude material (350 mg) was purified by flash chromatography by eluting with Petroleum Ether/EtOAc (from 0% to 100% and then till 5% MeOH in EtOAc) to afford the title compound as a regioisomeric mixture 75:25 (120 mg, 64%) as a yellow solid. LCMS (ES⁺) m/z 306 (M+H)⁺; RT 1.43 min.

Step 4: tert-butyl (4E)-4-[(R)-tert-butylsulfinyl]imino-1-methyl-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and tert-butyl (4E)-4-[(R)-tert-butylsulfinyl]imino-2-methyl-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate

A solution of tert-butyl 1-methyl-4-oxidanylidene-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and tert-butyl 2-methyl-4-oxidanylidene-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate (120 mg, 0.39 mmol) in Ti(OEt)₄ (1.24 mL, 5.89 mmol) was heated at 90° C. for 30 min under nitrogen. 2-methylpropane-2-sulfinamide (142 mg, 1.18 mmol) was added and the mixture was stirred at 90° C. for 48 h. After cooling down the mixture was poured in EtOAc (15 mL) and brine (5 mL) was added. The slurry was stirred for 15 min and filtered. The solution was then separated and the organic layer was washed with brine and dried over Na₂SO₄, filtered and concentrated in vacuo. The crude material (245 mg) was purified by flash chromatography by eluting with Petroleum Ether/EtOAc (from 0% to 100% and then till 5% MeOH in EtOAc) to afford the title compound as a regioisomeric mixture 90:10 (110 mg, 68%) as a white solid. LCMS (ES⁺) m/z 409 (M+H)⁺; RT 1.71 and 1.77 min.

Step 5: tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and tert-butyl (4R)-4-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (4E)-4-[(R)-tert-butylsulfinyl]imino-2-methyl-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and tert-butyl (4E)-4-[(R)-tert-butylsulfinyl]imino-1-methyl-spiro[6H-cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate (99 mg, 0.24 mmol) in THE (2 mL, 0.025 mol) under nitrogen was cooled at −50° C. and lithium aluminium hydride (654 uL, 1M in THF) was added dropwise. The resulting mixture was stirred for 2 h. Aqueous solution of Rochelle's salt (sodium potassium tartrate; 5 mL) was added while cooling and the resulting mixture extracted with EtOAc (2×20 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue (125 mg) was purified by flash chromatography eluting with Petroleum Ether/EtOAc (from 0% to 100%) to afford the desired product (58 mg, 58%) as a diasteroisomeric mixture. LCMS (ES⁺) m/z 411 (M+H)⁺; RT 1.79 min.

Step 6: 2-methyl-N-(2-methylspiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-4-yl)propane-2-sulfinamide

A solution of tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate and (4R)-4-[[(R)-tert-butylsulfinyl]amino]-2-methyl-spiro[4,6-dihydrocyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate (58 mg, 0.14 mmol) in DCM (1 mL) was treated dropwise with TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h. Mixture was concentrated in vacuo and used as a crude in the next step as a diasteroisomeric mixture. LCMS (ES⁺) m/z 311 (M+H)⁺; RT 0.6 min Intermediate 44 was used for the synthesis of Example 233.

Intermediate 45: 4-[(4-iodopyridin-3-yl)oxymethyl]-2-methyl-1,3-oxazole

A solution of 4-iodopyridin-3-ol (60 mg, 0.27 mmol), (2-methyloxazol-4-yl)methanol (31 mg, 0.27 mmol) and triphenylphosphine (85 mg, 0.33 mmol) in THE (6 mL, 0.04 M) was cooled to 0° C. then Diisopropyl (E)-1,2-diazenedicarboxylate (0.05 mL, 0.330 mmol) was slowly added. The mixture was stirred at 20° C. for 1 h, then MeOH (2 mL) was added and the solvent was concentrated under vacuo. The residue was purified by flash chromatography (from 0% to 100% EtOAc in DCM) to afford the title compound (33 mg, 38%). LCMS (ES⁺) m/z 317 (M+H)⁺, RT 1.12 min.

The Intermediate 45 was used to synthesize compound 227.

Intermediate 46: 3-chloro-4-iodo-2-(oxetan-3-yloxy)pyridine

Oxetan-3-ol (0.05 mL, 0.780 mmol) was dissolved in DMSO (0.78 mL, 0.5 M) and treated with dicesium carbonate (316 mg, 0.97 mmol), 3-chloro-2-fluoro-4-iodo-pyridine (100 mg, 0.390 mmol) and heated at 100° C. for 90 min. The mixture was diluted in EtOAc and washed with H₂O, dried over Na₂SO₄, filtered and evaporated in vacuo. The residue was purified by flash chromatography (from 0% to 100% EtOAc in Petroleum Ether) to afford the title compound (45 mg, 37%). (LCMS (ES⁺) m/z 312 (M+H)⁺; RT 1.79 min.

The Intermediate 46 was used to synthesize compound 153.

Intermediate 47: 3-chloro-4-iodo-N,N-dimethylpyridin-2-amine

A solution of N-methylmethanamine (583 uL, 1.17 mmol; 2M in THF) and 3-chloro-2-fluoro-4-iodo-pyridine (100 mg, 0.39 mmol) in DMSO (3 mL, 0.053 mol) was heated at 70° C. for 2 h. Water (2 mL) was added and mixture extracted with EtOAc (2×15 mL). Organic layer was washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue (210 mg) was purified by flash chromatography (from 0% to 100% EtOAc in Petroleum Ether) to afford the title compound (87 mg, 79%). LCMS (ES⁺) m/z 283 (M+H)⁺; RT 2.00 min.

The Intermediate 47 was used to synthesize compound 154.

Intermediate 48: (R)-2-methyl-N—((S)-5-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)propane-2-sulfinamide 2,2,2-trifluoroacetate

The compound was prepared according to the procedure reported below.

Step 1: tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl 6-morpholino-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (prepared as described in WO 2018/172984; 0.09 g, 0.230 mmol) in THF (1.8 mL) was treated with titanium ethoxide (0.1 mL, 0.460 mmol) followed by 2-methylpropane-2-sulfinamide (0.03 g, 0.270 mmol) at rt. The reaction mixture was stirred at 90° C. for 36 h. More titanium ethoxide (0.1 mL, 0.460 mmol) and 2-methylpropane-2-sulfinamide (0.03 g, 0.270 mmol) were added and the mixture stirred at 90° C. for further 36 h. After cooling the reaction mixture was diluted with EtOAc and NaHCO₃ sat sol and the mixture filtered on a pad of Celite. Phases were separated and the aqueous phase extracted with EtOAc (2×). The collected organics were dried over Na₂SO₄, filtered, and evaporated in vacuo to get the title compound as a yellow powder (110 mg, 99%). LCMS (ES⁺) m/z 512 (M+H+Na)⁺, RT 1.98 min.

Step 2: tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate

A solution of tert-butyl (R)-1-((tert-butylsulfinyl)imino)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (110 mg, 0.220 mmol) in THE (1.5 mL) cooled at −50° C. was treated with NaBH₄ (12.8 mg, 0.340 mmol) and the suspension was left warming to room temperature and stirred for 18 h. Formation of the desired product as two diasteroisomers in a ratio 89:11 was observed. The reaction mixture was treated with brine and extracted with EtOAc (2×). The collected organics were dried over Na₂SO₄, filtered and evaporated in vacuo to get a residue which was purified by flash chromatography (gradient elution 0-100% EtOAc in Petroleum Ether) to get the title compound in a ratio 87/13 with the R diasteroisomer as a white powder (83 mg, 75%). LCMS (ES⁺) m/z 492 (M+H)⁺, RT 2.00 min.

Step 3: (R)-2-methyl-N—((S)-5-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)propane-2-sulfinamide 2,2,2-trifluoroacetate

A solution of tert-butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (83 mg, 0.170 mmol) in DCM (1.5 mL) cooled to 0° C. was treated with TFA (0.13 mL) and the reaction mixture was left warming to rt and stirred for 2 h. Solvents were removed co-evaporating with toluene to get the title compound as a yellow powder (85 mg, 99%). LCMS (ES⁺) m/z 392 (M+H)⁺, RT 0.77 min.

Intermediate 45 was used for the synthesis of Example 223.

Biology

SHP2 Inhibition Enzymatic Assay

The assay was performed as described in Y P Chen et al, Nature (535)2016. Assay volume of 20 μL/well was assembled in 384 well black polystyrene low-binding microplates (Greiner), using the following buffer: 60 mM HEPES pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA pH 8, 0.05% tween-20, 5 mM DTT. The SHP-2 enzyme (synthetized by Origene, Met1-Leu525, cat #TP750155) was used at a final concentration of 0.5 nM. The enzyme was activated by 500 nM IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide SEQ ID No. 1) and incubated with 75 μM DiFMUP (Sigma) as substrate.

Briefly, DMSO serially diluted testing compounds were transferred to the bottom of the assay plate. SHP2 was then added together with the IRS1 peptide. 30 minutes post incubation, the DiFMUP substrate was added to the reaction and incubated 30 min at room temperature. Finally 5 μL of 160 μM bpV (Potassium bisperoxo[1,10-phenanthroline]oxovanadate [V], Sigma) were added to stop and quench the reaction. The fluorescence was detected by a microplate reader (Envision, PerkinElmer) according to the DiFMUP excitation and emission wavelength. The lower the fluorescence the higher the SHP2 inhibition.

The activity of each compound dilution was calculated as percentage of inhibition between vehicle (DMSO, 000 inhibition) and no enzyme (100% inhibition). The percentage inhibition is fitted against the compound dilutions with a four-parameter logistic regression. The inflection point (i.e. the concentration at which half-maximal inhibition is achieved) is the IC₅₀.

The IC₅₀ results of the compounds of the invention in the SHP2 inhibition enzymatic assay are shown in Table 2. Legend: A indicates IC₅₀ less or equal to 0.5 μM; B indicates IC₅₀ greater than 0.5 μM and lower or equal to 3 μM; C indicates IC₅₀ higher than 3 μM.

TABLE 2 SHP2 inhibition for compounds of the invention Example SHP2 wt - IC₅₀  1 A  2 A  3 A  4 B  5 B  6 B  7 B  8 B  9 B  10 B  11 B  12 B  13 B  14 B  15 C  16 B  17 B  18 A  19 A  20 A  21 B  22 A  23 A  24 A  25 B  26 B  27 C  28 A  29 C  30 C  31 B  32 C  33 A  34 B  35 A  36 B  37 A  38 A  39 A  40 C  41 C  42 B  43 B  44 B  45 B  46 B  47 B  48 B  49 A  50 B  51 C  52 A  53 C  54 B  55 B  56 B  57 C  58 B  59 B  60 A  61 A  62 A  63 B  64 B  65 C  66 C  67 C  68 C  69 B  70 A  71 A  72 C  73 A  74 A  75 C  76 B  77 A  78 B  79 B  80 B  81 B  82 C  83 C  84 B  85 B  86 B  87 C  88 A  89 B  90 B  91 B  92 A  93 B  94 A  95 A  96 A  97 B  98 A  99 A 100 B 101 C 102 C 103 A 104 C 105 B 106 C 107 A 108 C 109 C 110 C 111 C 112 C 113 C 114 A 115 B 116 B 117 C 118 A 119 B 120 C 121 C 122 B 123 C 124 A 125 B 126 A 127 B 128 A 129 B 130 A 131 B 132 A 133 A 134 A 135 A 136 A 137 C 138 C 139 A 140 B 141 A 142 B 143 A 144 B 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 B 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216 A 217 A 218 A 219 A 220 A 221 B 222 A 223 A 224 A 225 A 226 A 227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 B 237 A 238 A 239 A 240 A 241 B 242 B 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 C 251 A 252 A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264 A 265 A 266 A 267 A 268 A 269 A

Phospho-ERK Cellular Assay

ERK phosphorylation was detected using the “Advanced phospho-ERK1/2 (Thr202/Tyr204)” TR-FRET kit (Cisbio, Cat #64AERPEG/H), following the manufacturer reagents and instructions. Briefly, 20.000/well KYSE-520 cells (DSMZ ACC 371) were plated in 6 μL RPMI-1640 (Invitrogen) growth medium, into 384 white low-volume high base TC microplates (Greiner). After an overnight incubation, cells were treated with DMSO serial diluted compounds and incubated for 2 h at 37° C. After incubation, 2 μL/well of 4× Lysis Buffer (Cisbio 64KL1FDF), were added and incubated with cells for 30 min on gentle shaking. Finally, lysates were added with 2 μL/well of Eu cryptate (donor) and D2 (acceptor) conjugated antibodies (as provided by the Cisbio kit #64AERPEG/H) diluted 1:100 in Detection Buffer (as provided by the Cisbio kit #64AERPEG/H). Plates were then sealed and incubated at room temperature in the dark. After an overnight incubation, the TR-FRET signal was detected on a suitable reader (Envision, PerkinElmer). The lower the TR-FRET signal the higher the higher the SHP2 inhibition in cells. The activity of each compound dilution was calculated as percentage between vehicle DMSO treated cells and no cells, 0% inhibition and 100% inhibition respectively. The percentage activity is fitted against the compound dilutions with a four-parameter logistic regression. The inflection point (i.e. the concentration at which half-maximal inhibition is achieved) is the IC₅₀.

The IC₅₀ results of the compounds of the invention in the phospho-ERK cellular assay are shown in Table 3. Legend: “+” indicates IC₅₀ equal or higher than 5 μM; “++” indicates IC₅₀ less than 5 μM and higher or equal to 1 μM; “+++” indicates IC₅₀ less than 1 μM.

TABLE 3 pERK activity for compounds of the invention Example pERK IC₅₀  1 ++  2 ++  3 ++  18 ++  22 ++  35 +++  37 ++  52 +  60 ++  61 ++  62 ++  71 ++  74 ++  88 +  96 ++ 107 +++ 124 + 125 + 126 + 128 + 130 +++ 132 +++ 133 + 134 +++ 135 +++ 136 +++ 139 +++ 140 + 141 +++ 142 + 143 +++ 144 + 145 +++ 146 +++ 147 +++ 148 +++ 149 ++ 150 ++ 151 + 152 + 153 + 154 + 155 ++ 156 + 157 + 158 +++ 159 +++ 160 +++ 161 ++ 162 +++ 163 + 164 +++ 165 +++ 166 +++ 167 +++ 168 + 169 +++ 170 ++ 171 +++ 172 +++ 173 ++ 174 +++ 175 +++ 176 +++ 177 +++ 178 ++ 179 +++ 180 +++ 181 + 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 ++ 193 ++ 194 +++ 195 +++ 196 +++ 197 ++ 198 +++ 199 +++ 200 +++ 201 +++ 202 ++ 203 +++ 204 +++ 205 +++ 206 +++ 207 +++ 208 +++ 209 ++ 210 + 211 +++ 212 +++ 213 +++ 214 +++ 215 +++ 203 +++ 204 +++ 205 +++ 206 +++ 207 ++ 208 + 209 +++ 210 ++ 211 + 212 + 213 +++ 214 + 215 +++ 216 +++ 217 +++ 218 +++ 219 +++ 220 ++ 221 ++ 222 + 223 + 224 + 225 + 226 +++ 227 + 228 + 229 + 230 ++ 231 +++ 232 +++ 233 +++ 234 +++ 235 ++ 236 + 237 + 238 + 239 ++ 240 ++ 241 ++ 242 ++ 243 +++ 244 +++ 245 +++ 246 + 247 +++ 248 ++ 249 +++ 250 ++ 251 ++ 252 +++ 253 +++ 254 +++ 255 +++ 256 + 257 +++ 258 +++ 259 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 +++ 265 ++ 266 + 267 +++ 268 +++ 269 +++ 

1. A compound of Formula (I):

Wherein:

represents a single bond or a double bond; X₁ is N, S, O or NR_(3a); X₂ is N, NR_(3a) or CR_(3b); if X₁ is N then X₂ is NR_(3a); if X₁ is S, O or NR_(3a) then X₂ is N or CR_(3b); X₃ is N or CR_(x3) and R_(x3) is H, halogen or C₁₋₃alkyl; X₄ is N or CR₅; Y is S, O, NR₆, CH₂, CHF, CF₂, CHOH, C(O), SO, SO₂ or a single bond; R₁ and R₂ are each independently selected from: hydrogen; linear or branched C₁₋₁₂alkyl optionally substituted with one or more substituents independently selected from the group consisting of: OH, halogen, N(R₇)₂, aryl, heteroaryl, partially unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉heterocycloalkyl and spiro-C₃₋₈cycloalkyl ring optionally containing one heteroatom selected from the group consisting of O, N and S, wherein each of said aryl, heteroaryl, partially unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉ heterocycloalkyl and spiro-C₃₋₈cycloalkyl ring is optionally further substituted with one or more groups independently selected from the group consisting of: C(O)CH₃, C(O)OCH₃, heteroaryl, aryl, OH, halogen, NH₂, C₁₋₆alkyl, C₁₋₆alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃ alkylheteroaryl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, CN, haloC₁₋₆alkoxy, C₁₋₆alkoxy, C₅₋₇ heterocycloalkoxy and a cyclic amine selected from the group consisting of: pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, N-methylpyperazine and pyrrolidin-3-yloxy; and a cyclic structure selected from the group consisting of: C₃₋₇cycloalkyl, C₃₋₉ heterocycloalkyl, aryl, heteroaryl and partially unsaturated heteroaryl, each of said cyclic structure being optionally substituted with one ore more substituents independently selected from the group consisting of: halogen, C₁₋₃alkyl, C₁₋₃alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃ alkylheteroaryl, C(O)OC₁₋₃alkyl, C(O)C₁₋₃alkyl, N(R₇)₂, aryl and heteroaryl, each of said aryl or heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, C₁₋₃alkoxy and C₁₋₃haloalkyl; or R₁ and R₂ form together with the nitrogen atom to which they are attached a cyclic amine of formula (II)

wherein: m and n are each independently selected from 0, 1 and 2; W is absent, O, CR₈R₉, NR₁₀, S, SO or S02; R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a), R_(13b) are each independently selected from the group consisting of: H, C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy, halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₉ heterocycloalkyl; or any two of R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a), R_(13b) which are not germinal groups, taken together represent a single bond, a C₁₋₄alkanediyl or a C₂₋₄alkenediyl, each of said C₁₋₄alkanediyl or C₂₋₄alkenediyl being independently optionally substituted with one or more of C₁₋₄alkyl and/or halogen; said single bond or said optionally substituted C₁₋₄alkanediyl or C₂₋₄alkenediyl forming together with the bridging atoms to which they are respectively linked a 4-10 membered saturated or partially unsaturated ring; or any of R_(10a) and R_(10b), R_(11a) and R_(11b), R_(12a) and R_(12b) or R_(13a) and R_(13b) taken together with the carbon atom to which they are attached form a 3-7 membered saturated ring optionally containing one or more of O, S, N and/or C(O), the 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of halogen, OH, haloC₁₋₆alkyl, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C(O)OC₁₋₃alkyl and C(O)C₁₋₃alkyl; R₈ and R₉ are each independently selected from the group consisting of: H, OH, NH₂, aryl, heteroaryl, C₁₋₃alkylheteroaryl, C(O)NH₂, C₁₋₆alkyl, aminoC₁₋₆alkyl, NHCH₃ and NHSO₂CH₃; or R₈ and R₉ taken together with the carbon atom to which they are bound form a spiro-C₃₋₈ cycloalkyl ring of formula (III) as indicated below:

wherein: p and q are each independently selected from 0, 1 and 2; W₁ is absent, O, S, SO₂, CHF, CF₂ or NR_(w) and R_(w) is H, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of: aryl, heteroaryl, OH, C₁₋₃alkoxy and halogen; R_(14a), R_(14b), R_(15a), R_(15b), R_(16a), R_(16b), R_(17a), R_(17b) are each independently selected from the group consisting of: H, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆ alkyl, NHC(O)OC₁₋₆alkyl, halogen, OH, CN, C₁₋₃alkoxy, C₁₋₆alkyl optionally substituted with NH₂; or R_(15a) and R_(15b) taken together with the carbon atom to which they are bound form a spiro-C₃₋₆ cycloalkyl ring optionally containing a heteroatom selected from the group consisting of: N, O and S; or R_(15a) and R_(16a) are absent and R_(15b) and R_(16b) are joined together to form an aryl or heteroaryl ring, each being optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, CN, OH, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆ alkyl, haloC₁₋₆alkoxy, hydroxyC₁₋₆alkyl, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, N-methylpyperazine, C₃₋₉cycloalkyl; or R_(15b) and R_(16b) are joined together to form a C₅₋₇cycloalkyl or C₅₋₇heterocycloalkyl ring, each being independently optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆ alkyl, NHC(O)OC₁₋₆alkyl, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, CN, OH, ═O, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy and SO₂CH₃; R₁₀ is H, SO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆alkyl optionally substituted with one or more groups each independently selected from the group consisting of: OH, NH₂, NHC(O)C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, cyano, aryl and heteroaryl; or R₁₀ and R_(10a) are joined together to form a C₃₋₇heterocycloalkyl ring optionally containing another heteroatom selected from the group consisting of: N, S and O and optionally substituted with one or more groups each independently selected from the group consisting of: C₁₋₆alkyl, halogen, OH and CN; or R₁ and R₂ form together with the nitrogen atom to which they are attached a monocyclic or polycyclic heteroaryl or partially unsaturated heteroaryl ring, each of said ring is optionally substituted with one or more groups each independently selected from the group consisting of: halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH, CN, SO₂C₁₋₆alkyl, NH₂ and C(O)NH₂; R_(3a) is H, C₁₋₆alkyl, C₁₋₆alkyl-cycloalkyl or C₁₋₆alkyl-heterocycloalkyl, each of said groups being optionally substituted with one or more groups independently selected from the group consisting of: C₁₋₆alkoxy, hydroxyl, cyano, C(O)OC₁₋₆alkyl, C(O)NH₂, C(O)NHC₁₋₆alkyl; C(O)N(C₁₋₆ alkyl)₂, SO₂C₁₋₆alkyl, SOC₁₋₆alkyl, SO₂NHC₁₋₆alkyl and SO₂N(C₁₋₆alkyl)₂; R_(3b) is H, C₁₋₆alkyl, halogen, C(O)OC₁₋₆alkyl, hydroxyC₁₋₆alkyl or haloC₁₋₆alkyl; R₄ is a ring selected from the group consisting of: aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₆alkylaryl, C₁₋₆alkylheteroaryl and C₁₋₆alkylC₃₋₇cycloalkyl, each of said ring being optionally substituted with one or more groups each independently selected from the group consisting of: halogen, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆ alkyl-N(R₇)₂, C₂₋₇alkenyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, cyano-C₃₋₇cycloalkyl, —SF₅, C₅₋₇heterocycloalkoxy, optionally substituted aryl or heteroaryl, partially unsaturated heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryl-C₁₋₆alkyl, optionally substituted heteroaryl-C₁₋₆alkoxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)N(R₇)₂, C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl, N(R₇)₂ and oxo; R₅ is H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆heterocycloalkyl or NR_(x1)R_(x2) wherein R_(x1) and R_(x2) are each independently H or C₁₋₆alkyl, or R_(x1) and R_(x2) taken together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; R₆ is H or C₁₋₆alkyl; or R₄ and R₆ form together with the nitrogen atom to which they are attached a C₃₋₉ heterocycloalkyl, a heteroaryl or a partially unsaturated heteroaryl ring, each being optionally substituted with one or more groups independently selected from the group consisting of: OH, halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇ cycloalkoxy, aryl and heteroaryl; each R₇ is independently selected from the group consisting of: H, C₁₋₆alkyl, SO₂C₁₋₆alkyl, SOC₁₋₆ alkyl, C(O)OC₁₋₆alkyl, C(O)C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, C₁₋₆alkylaryl and C₁₋₆alkylheteroaryl; or two R₇ taken together with the nitrogen atom to which they are bound form a 3 to 7 membered cyclic amine optionally containing one additional heteroatom selected from the group consisting of S, N and O, said 3 to 7 membered cyclic amine being optionally substituted with one or more groups each independently selected from the group consisting of: OH, halogen, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl and C₃₋₇cycloalkoxy; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 2. The compound according to claim 1 wherein if X₄ is N then X₃ is CR_(x3) and if X₄ is CR₅ then X₃ is N, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 3. The compound according to claim 1, wherein: X₁ is N and X₂ is NR_(3a); or X₁ is NR_(3a) and X₂ is N; or X₁ is NR_(3a) and X₂ is CR_(3b); or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 4. The compound according to claim 1, wherein R₁ and R₂ are each independently selected from: hydrogen; linear or branched C₁₋₁₂alkyl optionally substituted with one or more substituents independently selected from the group consisting of: OH, halogen, N(R₇)₂, aryl, heteroaryl, partially unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉heterocycloalkyl and spiro-C₃₋₈cycloalkyl ring optionally containing one heteroatom selected from the group consisting of O, N and S, wherein each of said aryl, heteroaryl, partially unsaturated heteroaryl, C₃₋₉cycloalkyl, C₃₋₉ heterocycloalkyl and spiro-C₃₋₈cycloalkyl ring is optionally further substituted with one or more groups independently selected from the group consisting of: C(O)CH₃, C(O)OCH₃, heteroaryl, aryl, OH, halogen, NH₂, C₁₋₆alkyl, C₁₋₆alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, CN, haloC₁₋₆alkoxy, C₁₋₆alkoxy, C₅₋₇ heterocycloalkoxy and a cyclic amine selected from the group consisting of: pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, N-methylpyperazine and pyrrolidin-3-yloxy; and a C₃₋₇cycloalkyl, C₃₋₉heterocycloalkyl or a partially unsaturated heteroaryl selected from bicyclo[1.1.1]pentane, pirrolidine, piperidine, morpholine, piperazine, 2-azaspiro[3.3]heptane, azepan-2-one, 3-azaspiro[5.5]undecane, 2-azaspiro[4.5]decane, 3-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 6′,7′-dihydrospiro[azetidine-3,5′-pyrrolo[1,2-a]imidazole], 5-azaspiro[3.5]nonane, 1-thia-7-azaspiro[3.5]nonane 1,1-dioxide, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[2.1.1]hexane, 6-azabicyclo[3.2.1]octane, octahydroindole, octahydro-1H-isoindole, 5-oxa-2-azaspiro[3.4]octane and 1,2,3,4-tetrahydroquinoline, each of said groups being optionally substituted with one ore more substituents independently selected from the group consisting of: halogen, C₁₋₃alkyl, C₁₋₃alkyl-N(R₇)₂, C₁₋₃alkylaryl, C₁₋₃alkylheteroaryl, C(O)OC₁₋₃alkyl, C(O)C₁₋₃alkyl, N(R₇)₂, aryl and heteroaryl, each of said aryl or heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, C₁₋₃alkoxy and C₁₋₃haloalkyl; or R₁ and R₂ form together with the nitrogen atom to which they are attached a cyclic amine of formula (II)

wherein: m and n are each independently selected from 0, 1 and 2; W is absent, O, CR₈R₉, NR₁₀, S, SO or S02; R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a), R_(13b) are each independently selected from the group consisting of: H, C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy, halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₉ heterocycloalkyl; or any two of R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a), R_(13b) which are not germinal groups, taken together represent a single bond, a C₁₋₄alkanediyl or a C₂₋₄alkenediyl, each of said C₁₋₄alkanediyl or C₂₋₄alkenediyl being independently optionally substituted with one or more of C₁₋₄alkyl and/or halogen; said single bond or said optionally substituted C₁₋₄alkanediyl or C₂₋₄alkenediyl forming together with the bridging atoms to which they are respectively linked a 4-10 membered saturated or partially unsaturated ring; or any of R_(10a) and R_(10b), R_(11a) and R_(11b), R_(12a) and R_(12b) or R_(13a) and R_(13b) taken together with the carbon atom to which they are attached form a 3-7 membered saturated ring optionally containing one or more of O, S, N and/or C(O), the 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of halogen, OH, haloC₁₋₆alkyl, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C(O)OC₁₋₃alkyl and C(O)C₁₋₃alkyl; R₈ and R₉ are each independently selected from the group consisting of: H, OH, NH₂, aryl, heteroaryl, C₁₋₃alkylheteroaryl, C(O)NH₂, C₁₋₆alkyl, aminoC₁₋₆alkyl, NHCH₃ and NHSO₂CH₃; or R₈ and R₉ taken together with the carbon atom to which they are bound form a spiro-C₃₋₈ cycloalkyl ring of formula (III) as indicated below:

wherein: p and q are each independently selected from 0, 1 and 2; W₁ is absent, O, S, SO₂, CHF, CF₂ or NR_(w) and R_(w) is H, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of: aryl, heteroaryl, OH, C₁₋₃alkoxy and halogen; R_(14a), R_(14b), R_(15a), R_(15b), R_(16a), R_(16b), R_(17a), R_(17b) are each independently selected from the group consisting of: H, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆ alkyl, NHC(O)OC₁₋₆alkyl, halogen, OH, CN, C₁₋₃alkoxy, C₁₋₆alkyl optionally substituted with NH₂; or R_(15a) and R_(15b) taken together with the carbon atom to which they are bound form a spiro-C₃₋₆cycloalkyl ring optionally containing a heteroatom selected from the group consisting of: N, O and S; or R_(15a) and R_(16a) are absent and R_(15b) and R_(16b) are joined together to form an aryl or heteroaryl ring, each being optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, CN, OH, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆ alkyl, haloC₁₋₆alkoxy, hydroxyC₁₋₆alkyl, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, N-methylpyperazine, C₃₋₉cycloalkyl; or R_(15b) and R_(16b) are joined together to form a C₅₋₇cycloalkyl or C₅₋₇heterocycloalkyl ring, each being independently optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, NH₂, NHSOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, NHC₁₋₆ alkyl, N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)OC₁₋₆alkyl, CN, OH, ═O, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, SO₂CH₃; R₁₀ is H, SO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl or C₁₋₆alkyl optionally substituted with one or more groups each independently selected from the group consisting of: OH, NH₂, NHC(O)C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, cyano, aryl and heteroaryl; or R₁₀ and R_(10a) are joined together to form a C₃₋₇heterocycloalkyl ring optionally containing another heteroatom selected from the group consisting of: N, S and O and optionally substituted with one or more groups each independently selected from the group consisting of: C₁₋₆alkyl, halogen, OH and CN; or R₁ and R₂ form together with the nitrogen atom to which they are attached a monocyclic or polycyclic heteroaryl or partially unsaturated heteroaryl ring selected from the group consisting of: pyrrole, pyrazole, indole, benzimidazole, 2H-pyrazolo[3,4-b]pyridine, indazole, 2H-pyrazolo[3,4-c]pyridine, 6H-pyrrolo[3,4-b]pyridine, 6H-pyrrolo[3,4-b]pyrazine, 6H-pyrrolo[3,4-d]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine and 1,2,3,4-tetrahydroquinoline, and each of said ring is optionally substituted with one or more groups each independently selected from the group consisting of: halogen, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH, CN, SO₂C₁₋₆alkyl, NH₂ and C(O)NH₂; each of R_(3a) and R_(3b) is independently H or C₁₋₆alkyl; R₄ is a ring selected from the group consisting of: phenyl, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine, quinoline, indazole, benzothiophene, isoquinoline, thiophene, imidazopyridine, naphthyridine, quinazoline, benzimidazole, indoline, isoindoline, 1,3-dihydroisobenzofuran, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, quinazolin-4(3H)-one, indolin-2-one and 2,3-dihydro-1H-inden-1-one, indole, dihydroquinoline, dihydroquinolin-2-one, imidazo[1,2-a]pyridine, pyrido[2,3-b]pyrazine, indazole, benzo[c][1,2,5]oxadiazole, pyridine-2(1H)-one and pyrrolo[2,3-b]pyridine each of said ring being optionally substituted with one or more groups each independently selected from the group consisting of: halogen, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆ alkyl-N(R₇)₂, C₂₋₇alkenyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₃₋₇cycloalkyl, cyano-C₃₋₇ cycloalkyl, —SF₅, C₅₋₇heterocycloalkoxy, optionally substituted aryl or heteroaryl, partially unsaturated heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryl-C₁₋₆alkyl, optionally substituted heteroaryl-C₁₋₆alkoxy, C(O)OH, C(O)OC₁₋₆alkyl, C(O)N(R₇)₂, C(O)C₁₋₆ alkyl, C₁₋₆alkylCOOH, SO₂C₁₋₆alkyl, N(R₇)₂ and oxo; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 5. The compound according to claim 1, having general Formula (IA), (IB) or (IC):

wherein: X₃, X₄, Y, R₄, m, n, W, R_(10a), R_(10b), R_(11a), R_(11b), R_(12a), R_(12b), R_(13a) and R_(13b) are as defined in claim 1, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 6. The compound according to claim 1, wherein X₃ is N and X₄ is CR₅.
 7. The compound according to claim 1, wherein R₁ and R₂ together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of: aziridine, azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine, piperazine, 1,4-diazepane, 1,5-diazocane, 8-azaspiro[4.5]decane, 1,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, 1,7-diazaspiro[3.5]nonane, 1-oxa-3,7-diazaspiro[4.5]decan-2-one, (1S,4S)-2,5-diazabicyclo[2.2.2]octane, 1-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,3-dihydrospiro[indene-2,4′-piperidine], 5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine], 5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine], 5,6,7,8-tetrahydro-1,6-naphthyridine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, 3,9-diazabicyclo[4.2.1]nonane, 3,8-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 2,6-diazaspiro[3.4]octane, 3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane, 5-oxa-2,8-diazaspiro[3.5]nonane, 3,9-diazabicyclo[3.3.1]nonane, 1,2,3,4-tetrahydroisoquinoline, 1-oxa-4,8-diazaspiro[5.5]undecane, hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, 2-azaspiro[3.4]octane, 5-azaspiro[3.4]octane, 2,7-diazaspiro[4.6]undecane, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 1-oxa-9-azaspiro[5.5]undecane, 6,8-diazaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, tetrahydro-1H,4H-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole, 8-oxa-2-azaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decane, 1-oxa-4-azaspiro[5.5]undecane, 8-thia-2-azaspiro[4.5]decane 8,8-dioxide, 3′,4′-dihydro-2′H-spiro[azetidine-3,1′-pyrrolo[1,2-a]pyrazine], 2,6-diazabicyclo[3.2.2]nonane, 2,7-diazaspiro[4.4]nonane, 3H-spiro[benzofuran-2,4′-piperidine], 2-methyl-2,6-dihydro-4H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine], 4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine]; each of said cyclic amine being optionally substituted with one or more substituents each independently selected from the group consisting of: C₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkoxy, halogen, NH₂, CN, OH, C(O)NH₂, heteroaryl, optionally substituted aryl, hydroxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₉heterocycloalkyl; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 8. The compound according to claim 1, wherein Y is S or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 9. The compound according to claim 1, wherein R₄ is an aryl or heteroaryl ring selected from the group consisting of: phenyl, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine, quinoline, isoquinoline, indolin-2-one, indoline, isoindoline, indole, naphtyridine, benzimidazole, dihydroquinoline, dihydroquinolin-2-one, imidazo[1,2-a]pyridine, pyrido[2,3-b]pyrazine, indazole, benzo[c][1,2,5]oxadiazole, pyridine-2(1H)-one and pyrrolo[2,3-b]pyridine and each of said aryl or heteroaryl ring is optionally independently substituted with one or more groups each independently selected from the group consisting of: halogen, cyano, NH₂, CF₃, NHCH₃, NHCOCH₃, C₁₋₆alkoxy, N(CH₃)₂, —NHcycloalkyl, C₁₋₆alkyl-NH2, heteroaryl-C₁₋₆alkoxy, trifluromethoxy, C(O)N(R₇)₂ cyclopropanamine, cyclobutanamine, azetidine and pyrrolidine, each of said cyclopropanamine, cyclobutanamine, azetidine or pyrrolidine being optionally substituted with one or more groups independently selected from the group consisting of: OH, halogen, cyano and methyl; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 10. A compound according to claim 1 selected from the group consisting of: 4-methyl-1-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine (8-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)methanamine (R)-8-(6-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine 2-(1,7-diazaspiro[3.5]nonan-7-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine 1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 2-(4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 4-methyl-1-(6-(phenylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(5-((2-(trifluoromethyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-(trifluoromethyl)benzonitrile 1-(5-((2,4-difluorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2,3-difluorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 2-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzonitrile 1-(5-((2-methoxyphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-3-amine N-(piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine 1-(5-((2-bromophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((4-chloro-2-methylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2,3-dimethylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 2-(1,7-diazaspiro[3.5]nonan-1-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine 4-methyl-1-(5-((6-(trifluoromethyl)pyridin-2-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(5-((3-(2-methylthiazol-4-yl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(6-(quinolin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(1-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-([1,1′-biphenyl]-3-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-methyl-1-(5-(naphthalen-1-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(5-(quinolin-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-((1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2-bromopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-(isoquinolin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-methyl-1-(5-(quinoxalin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-((2-chlorothiophen-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-methyl-1-(5-((2-(pentafluoro-16-sulfaneyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-methyl-1-(5-(naphthalen-2-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 4-methyl-1-(5-(quinolin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-(isoquinolin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-methyl-1-(5-((3-(pentafluoro-16-sulfaneyl)phenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 3-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzoic acid 4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)benzoic acid (3S,4S)-3-methyl-8-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine 4-methyl-1-(5-((8-(trifluoromethyl)quinolin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)piperidin-4-amine 1-(5-((2-chlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 4-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chlorobenzoic acid 2-(3-((2-(4-amino-4-methylpiperidin-1-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)phenyl)acetic acid 1-(5-((1,8-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 1-(5-((3-chloro-2-methylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine 1-(5-((2-isopropylphenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-methylpiperidin-4-amine (S)-1′-(6-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 2-(9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine 2-(3,9-diazabicyclo[4.2.1]nonan-3-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazine N-(5-azaspiro[3.5]nonan-8-yl)-6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine (8-(6-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)methanamine N-((5-phenylpyrrolidin-3-yl)methyl)-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-amine (S)-1′-(6-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoro-1-methylindolin-2-one (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoroindolin-1-yl)ethan-1-one (S)-1′-(5-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2-(trifluoromethyl)pyridine 1-oxide (R)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine 1-(2-((2,3-dichlorophenyl)thio)-7H-purin-8-yl)-4-methylpiperidin-4-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)—N-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)acetamide (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (R)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-ol (S)-1′-(5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (R)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (S)-1′-(5-((4-(trifluoromethyl)pyrimidin-5-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-8-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2H-benzo[b][1,4]oxazin-3(4H)-one (S)-1′-(5-((3-chloropyrazin-2-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,3-difluoroindolin-2-one (R)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[furo[3,2-b]pyridine-2,4′-piperidin]-3-amine (S)-1′-(6-((1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidin-3-ol (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-3-chloro-1-methylpyridin-2(1H)-one (S)-1′-(6-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-6-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-4-chlorobenzo[d]oxazol-2(3H)-one (S)-6-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (S)-5-((2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3,4-dihydroquinolin-2(1H)-one (S)-1′-(5-((2,3-dichloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-8-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-(quinolin-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-7-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)thio)benzo[d]oxazol-2(3H)-one (S)-1′-(5-(quinoxalin-5-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloro-2-morpholinopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloro-2-(3-methoxyazetidin-1-yl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-6-fluoro-1′-(6-((3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((2-amino-5-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-6-fluoro-1′-(6-((3-fluoropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((2-amino-3-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1-(4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonitrile (S)-6-fluoro-1′-(5-(imidazo[1,2-a]pyridin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((1H-indol-6-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-(pyrido[2,3-b]pyrazin-8-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((3-chloro-2-methylpyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine (R)-1′-(5-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine (S)-1′-(6-((1H-indol-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-ethoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-2-(methylamino)nicotinonitrile (S)-1′-(5-((2-methyl-2H-indazol-7-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(6-((2-amino-3-methylpyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-ol (R)—N—((S)-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (S)-1′-(5-((3-aminopyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-(dimethylamino)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-(thieno[3,2-b]pyridin-7-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-(benzo[c][1,2,5]oxadiazol-4-ylthio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-2-amino-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)nicotinonitrile (S)-5-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)quinoxalin-2(1H)-one (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)picolinonitrile (S)-1′-(5-((5-fluoroquinolin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((6-methoxy-1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-4H-pyrido[1,2-a]pyrimidin-4-one (S)-1′-(5-((2-amino-3-fluoropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-N-methylpicolinamide (S)-1′-(5-((2-(pyrrolidin-1-yl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-(trifluoromethoxy)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-((2-methyloxazol-4-yl)methoxy)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-6-bromo-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-3-fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-6-bromo-1′-(5-((2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-2-methyl-2,6-dihydro-4H-spiro[cyclopenta[c]pyrazole-5,4′-piperidin]-4-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)pyridazin-3(2H)-one (S)-1′-(5-((2-(oxazol-2-ylmethoxy)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-methoxypyridazin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((4-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-3-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)pyridin-2(1H)-one (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (S)-4-((2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)thio)-5-chloropyridin-2-ol (S)-1′-(5-((5-chloro-2-methoxypyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-(1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)methanol (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-(fluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloro-2-(ethylamino)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((3-chloropyridazin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(7-chloro-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((5-(aminomethyl)-2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-(1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-5-yl)methanol methyl (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (S)-1′-(5-((8-methyl-1,5-naphthyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-6-cyclopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-2-chloro-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine (S)-1′-(6-chloro-5-((2,3-dichlorophenyl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (R)-1-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile (S)-1′-(5-((1-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((2-chloro-3-(trifluoromethyl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine (S)-1′-(5-((2-(methylamino)-3-(trifluoromethyl)pyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(5-((6-amino-2,3-dichloropyridin-4-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (S)-1′-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine (3S,4S)-8-(2-((2-amino-3-chloropyridin-4-yl)thio)-5H-pyrrolo[2,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; and (S)-1′-(5-((6-amino-2-methoxypyridin-3-yl)thio)-1H-imidazo[4,5-b]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.
 11. (canceled)
 12. A method of inhibiting SHP2 activity, comprising administering a therapeutically effective amount of a compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof according to claim 1 to a patient in need thereof.
 13. A method for salt the treatment and/or prevention of a disease or disorder mediated by the activity of SHP2 comprising administering a therapeutically effective amount of a compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof according to claim 1 to a patient in need thereof.
 14. A method for the treatment and/or prevention of a disease or disorder selected from the group consisting of: cancer, cardiovascular disease, immunological disorder, fibrosis, an ocular disorder, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof, comprising administering a compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof according to claim 1 to a patient in need thereof.
 15. The method according to claim 13, wherein the disease or disorder is selected from the group consisting of: Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and combinations thereof.
 16. The method according to claim 14 wherein any of said cancers is a primary cancer or a cancer metastasis.
 17. The method according to claim 14, further comprising administering said compound in combination with radiotherapy or with at least one further therapeutic agent, preferably said at least one further therapeutic agent is selected from the group consisting of: (a) alkylating agents, including but not limited to carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN); (b) anti-metabolites, including but not limited to cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX) and raltitrexed; (c) antimitotics, which are often plant alkaloids and terpenoids, or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunine; (d) checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors that target LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumour necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3) and/or OX40 (tumour necrosis factor receptor superfamily member 4); (e) topoisomerase inhibitors, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON) and etoposide (EPOSIN); (f) cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR) and exemestane (AROMASIN); (g) angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN); (h) anti-steroids and anti-androgens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) and nilutamide (NILANDRON); (i) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatininb (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; (12) monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) other agents, such as amsacrine; Bacillus Calmette-Gudrin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p′-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione and combinations thereof.
 18. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof of claim 1, alone or in combination with at least one further therapeutic agent, and at least one pharmaceutically acceptable excipient, preferably said at least one further therapeutic agent is selected from the group consisting of: (a) alkylating agents, including but not limited to carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN); (b) anti-metabolites, including but not limited to cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX) and raltitrexed; (c) antimitotics, which are often plant alkaloids and terpenoids, or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunine; (d) checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors that target LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumour necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3) and/or OX40 (tumour necrosis factor receptor superfamily member 4); (e) topoisomerase inhibitors, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON) and etoposide (EPOSIN); (f) cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR) and exemestane (AROMASIN); (g) angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN); (h) anti-steroids and anti-androgens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) and nilutamide (NILANDRON); (i) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatininb (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; (12) monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) other agents, such as amsacrine; Bacillus Calmette-Gudrin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p′-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione and combinations thereof.
 19. (canceled)
 20. A process for the synthesis of the compound of Formula (I) or the pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined in claim 1, said process comprising at least one of the following steps: a) reacting a compound of formula (A) with a compound of formula R₄YH in the presence of a transition metal catalyst or under photochemical conditions, wherein said transition metal catalyst is preferably a palladium or copper catalyst, such as Pd₂(dba)₃, Pd(PPh₃)₄ and CuI:

b) when in said compound of Formula (I) Y is S, reacting in a first step a compound of formula (A) with 2-ethylhexyl 3-mercaptopropanoate in the presence of a palladium catalyst, and further reacting in a second step the product from the first step with a compound of formula R₄X, wherein X is bromide, chloride, iodide or triflate, in the presence of a palladium catalyst, wherein said first and second steps are carried out in the presence of a tertiary amine, preferably DIPEA or TEA, and wherein the palladium catalyst in said first and/or second step is preferably Pd₂(dba)₃ or Pd(PPh₃)₄:

or c) when in said compound of Formula (I) Y is a bond, reacting a compound of formula (A) with R₄-boronic acid in the presence of a palladium catalyst, preferably Pd(PPh₃)₄, and a base:

or d) reacting a compound of formula (B), wherein Lg is a leaving group selected from the group consisting of halogen, SO₂Me and SOMe, with an amine of formula R₁R₂NH at temperature range of about 100° C. to about 120° C.:

wherein in each of said a), b) c) or d) steps, if X₁ or X₂ is NH, it can be optionally protected for example as a trimethylsilylethoxymethyl (SEM) derivative. 